November 2022 Science Journal Highlights

November 2022 is coming to an end, what are the highlights of the Science journal worth learning in November? The editor has sorted out this and shared
it with you.

1.
Science: The universal flu vaccine has a show! Developed an experimental mRNA vaccine against all 20 known influenza virus subtypes

doi:10.
1126/science.
abm0271

In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania in the United States found that an experimental mRNA vaccine against all 20 known influenza virus subtypes offered broad protection against other deadly influenza virus strains in initial tests and could one day become a universal measure
to prevent future influenza pandemics 。 The results were published in the Nov.
25, 2022 issue of Science under the title "Cortical wiring by synapse type–specific control of local protein synthesis.
"

20-HA mRNA-LNP antigen
.
Image from Science, 2022, doi:10.
1126/science.
abm0271
.

The strategy employed by these authors was inoculation with immunogens from all known influenza virus subtypes--- a class of antigens that stimulate the immune response to elicit ---broad protection
.
The vaccine they developed is not expected to provide the sterilizing immunity that completely protects against viral infections
.
Instead, the new study shows that the vaccine elicits a memory immune response that can be rapidly activated and adapted to new pandemic influenza virus strains, significantly reducing severe illness and death
from infection.

Dr.
Scott Hensley, corresponding author and professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania, said, "The idea is to give people a baseline level of immune memory of different influenza virus strains, so that when the next influenza pandemic occurs, illness and death will be greatly reduced
.
" Hensley and his lab collaborated with the lab of Dr.
Drew Weissman, a pioneer in mRNA vaccines and director of vaccine research at the University of Pennsylvania's Perelman School of Medicine
.

2.
Two Science reveals that RNA-guided cleavage of CRISPR-Cas effector proteins can trigger adaptive immune responses

doi:10.
1126/science.
add7450; doi:10.
1126/science.
add7347

In the first new study, researchers from the Massachusetts Institute of Technology demonstrated that the CRISPR-associated protease Csx29 exhibits programmable RNA-activated endopeptidase activity against factor σ inhibitors to regulate transcriptional responses
.
The cryo-EM structure of the active substrate-bound Csx29 complex reveals a heterogeneous activation mechanism that recombines catalytic residues of Csx29 upon target RNA binding
.
The findings were published in the Nov.
26, 2022 issue of Science in the paper "RNA-activated protein cleavage with a CRISPR-associated endopeptidase.
"
This discovery reveals an RNA-guided function in nature that can be used for RNA detection applications
in vitro and in human cells.

In a second new study, researchers from the Massachusetts Institute of Technology in the United States and the University of Tokyo in Japan found that the type III-E CRISPR system includes the proteinease Csx29, similar to caspase, which is activated to cleave another helper protein
called Csx30 when Cas7-11 recognizes the target RNA.
This cleavage produces toxic Csx30 fragments that are hypothesized to inhibit specialized σ factor RpoE, regulate the bacterial response to phage infection, and cause bacterial growth arrest, thereby clearing phage infection
。 The findings were published in the Nov.
26, 2022 issue of Science in the paper "RNA-triggered protein cleavage and cell growth arrest by the type III-E CRISPR nuclease-protease.
"

They also reported the cryo-EM structure of the Cas7-11-crRNA-Csx29 complex in the presence and absence of target RNA, and demonstrated that binding of target RNA induces conformational changes
in Csx29.
Biochemical experiments have shown that cleavage of Csx29 to the helper protein Csx30 is target RNA-dependent
.
The recombination of this system in bacteria shows that cleavage of Csx30 produces toxic protein fragments that lead to growth arrest, which is regulated by Csx31
.
Csx30 binds to Csx31 and the related σ factor RpoE, suggesting that Csx30-mediated σ factor RpoE inhibition regulates bacterial cell response
to phage infection.
We program the Cas7-11-CSX29-CSX30 system for programmable RNA detection
in mammalian cells.
These findings expand the known complexity of CRISPR immune responses, enabling protease-based programmable RNA detection in mammalian cells
.
Overall, the Cas7-11-Csx29 effector protein is an RNA-dependent nuclease-protease
.

3.
Science: Revealing the mechanism by which the totipotent pioneer factor Nr5a2 activates the genomic mechanism of fertilized eggs

doi:10.
1126/science.
abn7478

Sperm fertilizing an egg is the beginning of
a new life.
The genetic information of the mother and the father, which together store the body structure of the organism, are combined
after fertilization.
However, in this early stage of life, DNA remains inactive in the nucleus
.
Although the first division of a fertilized egg cell takes place with the help of maternal factors stored in the egg, the synthesis of new embryonic products is necessary for the further development of the embryo, which requires exposure to embryonic DNA
.
In a new study, Kikuë Tachibana and her research team at the Max Planck Institute for Biochemistry in Germany confirmed that the totipotent pioneer factor Nr5a2 activates embryonic DNA
.
The results of the study were published online in the journal Science on November 24, 2022, in the paper "Zygotic genome activation by the totipotency pioneer factor Nr5a2"
.

Imre Gáspár, co-first author and expert in microscopy and bioinformatics at the Max Planck Institute of Biochemistry, explains, "We looked for common sequence patterns for early mRNA molecules produced in embryos and were able to find several sequence motifs
.
The sequence motifs we found are close to each other, forming a so-called supermotif.

This newly discovered supermotif is similar to the known sequence motif SINE B1 element and is very closely related
to the highly conserved ALU element in the human genome.
These elements are also known as 'jumping genes' because they can move from one location of the genome to another at certain cellular stages, such as early embryos
.
”

Nr5A2 binds to this supermotif.

Johanna Gassler, an embryologist at the Max Planck Institute for Biochemistry and co-first author of the paper, said, "Initially, Nr5a2 was found in the liver
.
In the field of developmental biology, it is known that Nr5a2 is important
in the later stages of embryo implantation.
Exactly how important NR5a2 is after fertilization is unknown
.
In our experiments, we were able to find that once Nr5a2 is blocked, most early embryonic mRNA molecules are no longer produced
.
In addition, the further development of the embryo is also inhibited
.
This suggests that Nr5a2 plays a central role
in the earliest stages of embryonic development.
”

4.
Science: Significant progress! Revealing spermidine-enhanced anti-tumor immune response mechanism

doi:10.
1126/science.
abj3510

In mammals, the strength of the immune system declines
with age.
This is due to a variety of factors, including reduced T cell antigen pool output and diversity due to thymic degeneration; Changes in cellular metabolism caused by inflammation; and defects
in the proliferation, differentiation, or viability of T cells.
Older adults often suffer from severe infections and cancers, and the therapies applied--- including PD-1 blockade in cancer immunotherapy--- are often ineffective for them compared to outcomes in younger patients
.
As a biopolyamine, spermidine (SPD) decreases with age, and supplementation with SPD has been shown to improve or delay several age-related disorders, including immune system disorders
.
The proposed mechanisms for rejuvenating the immune system through SPD include enhanced autophagy, translational activity, and mitochondrial metabolism
.
Previously, SPD supplementation has been shown to enhance anti-tumor immune responses
in animal models.
However, the relationship between SPD deficiency and age-induced T cell immunosuppression remains largely unknown
.

SPD binds to MTP and activates fatty acid oxidation
in T cells.
Image from Science, 2022, doi:10.
1126/science.
abj3510
.

Given that CD8+ T cells play a key role in tumor immunity, researchers from Kyoto University, Tohoku University and the Institute of Physics and Chemistry in Yokohama, Japan, have studied how aging affects the metabolic and functional characteristics
of CD8+ T cells in a new study.
They explored whether insufficient SPD was a factor
in the failure of older mice to respond to PD-1 antibody therapy.
They sought to characterize the CD8+ T cell population changes induced by SPD supplementation in aged mice and to determine the molecular mechanism
of SPD's action.
The results of the study were published in the October 28, 2022 issue of Science under the title "The mechanism of acentrosomal spindle assembly in human oocytes.
"

The authors found that the total concentration of SPD and intracellular free concentration in CD8+ T cells of aged mice were about half
that of young mice.
In terms of bioenergetics, older CD8+ T cells showed impaired mitochondrial activity and lower
oxygen consumption rates, ATP production, and fatty acid oxidation (FAO) activity compared to young CD8+ T cells.

These authors demonstrated that SPD supplementation enhanced the antitumor activity
of PD-1-blocking immunotherapy in elderly mice.
SPD supplementation has also proven effective
against young mice whose tumors did not respond to single anti-PD-L1 antibody therapy.
The combination therapy with SPD and anti-PD-L1 antibodies enhances CD8+ T cell proliferation, cytokine production, and mitochondrial ATP production
in vivo.
In vitro, SPD effectively enhances mitochondrial function and metabolizes palmitic acid to a tricarboxylic acid cycle component within 1 hour, suggesting that SPD has the potential to bind
directly to mitochondria-associated proteins.
Biochemical analysis determined that SPD binds to mitochondrial trifunctional protein (MTP), a core enzyme
for fatty acid β-oxidation.
MTP consists of α and β subunits, both of which bind
to SPD.
Several experiments using MTP synthesized and purified from Escherichia coli have shown that SPD binds to MTP with strong affinity [binding affinity (dissociation constant, Kd) = 0.
1 μM] and isostructively enhances its enzymatic fatty acid oxidation activity
.
In addition, they found that spermine, another polyamine derived from SPD, has important cytoprotective functions, also binds directly to MTP, and competitively inhibits the fatty acid oxidative activity of SPD, suggesting that the balance of SPD and spermine is important
for assessing fatty acid oxidative activity in aged cells.
Specific elimination of MTP α subunits in T cells eliminated the potentiating effect of SPD on PD-1-blocking immunotherapy, suggesting that MTP is required for
SPD-dependent T cell activation.

5.
Science: Reveal that mammalian oocytes use mitochondria-associated membrane-free compartments to store maternal mRNA

doi:10.
1126/science.
abq4835

Mammalian oocytes accumulate large amounts of messenger RNA (mRNA)
through active transcription during growth.
Transcription stops at the final stage of oocyte growth and resumes
only when the embryonic genome is activated after fertilization.
During this time, oocytes and embryos can only use stored mRNA to synthesize new proteins
.
Therefore, proper storage of maternal mRNA is essential
for oocytes to mature into fertilizable eggs through meiosis and early embryonic development after fertilization.
However, where and how maternal mRNA is stored in mammalian oocytes, including human ones, remains a mystery
.

RNA is typically stored in membrane-free compartments, which are formed
by spontaneous phase separation of proteins and/or nucleic acids.
Previous studies have identified different types of membrane-free compartments for storing mRNA in non-mammalian oocytes, such as P granules in Caenorhabditis elegans and Polar granules
in fruit flies.
So, in a new study, researchers from the Max Planck Institute for Multidisciplinary Science in Germany set out to identify potential RNA storage compartments
in mammalian oocytes.
The results were recently published in the journal Science as "Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment.
"

MARDO
in mouse oocytes.
Image from Science, 2022, doi:10.
1126/science.
abq4835
.

The authors analyzed the localization
of highly expressed RNA-binding proteins in mouse oocytes.
They found that the RNA-binding proteins ZAR1, YBX2, DDX6, LSM14B, and 4E-T (EIF4ENIF1) co-locate with mitochondria to form clusters in the cytoplasm
.
In contrast, they are not colocated with the Golgi apparatus, recycling endosomes, or lysosomes, but only partially with the endoplasmic reticulum
.
In addition, they stained the mRNA with RNA fluorescence in situ hybridization and found that they were stored in
this mitochondria-associated membrane-free compartment.
This domain is also present in oocytes of other mammalian species, including humans
.
Because this domain is different from any known RNA-containing compartment, they named it the mitochondria-associated ribonucleoprotein domain (MARDO
).

MARDO assembly around the
mitochondria is guided by an increase in mitochondrial membrane potential during oocyte growth.
MARDO emerges gradually as oocytes grow and becomes most pronounced in fully grown oocytes, which are also the most
active mitochondria.
Among the RNA-binding proteins localized in MARDO, ZAR1 plays a major role
in MARDO assembly.
ZAR1, rather than other RNA-binding proteins, promotes the condensation of MARDO foci into a hydrogel-like matrix when
overexpressed.
MARDO condensation pushes mitochondria to aggregate into huge clusters
.
Through a series of in vivo and in vitro experiments, these authors found that the unstructured N-terminal domain of ZAR1 is essential
for MARDO assembly and its binding to mitochondria.
They culled ZAR1 through gene knockouts, RNA interference, and Trim-Away, and found that both MARDO formation and mitochondrial aggregation were impaired
.
By expressing ZAR1 in Zar1 knocked out oocytes, MARDO formation and mitochondrial aggregation are restored
.
These results confirm that ZAR1 is essential
for MARDO assembly and mitochondrial aggregation.
In addition, live-cell imaging analysis revealed severe defects
in spindle assembly, chromosome arrangement, and cell division during oocyte meiotic maturation due to ZAR1 deletion.

MARDO stores translation-inhibited mRNAs, some of which are known to be activated and protein expressed
during or after fertilization of oocytes into fertilizable eggs.
ZAR1 LOSS NOT ONLY DESTROYS MARDO, BUT ALSO LEADS TO PREMATURE LOSS OF MRNA LOCALIZED IN MARDO
.
Maternal mRNA needs to be progressively degraded and replaced by mRNA transcribed from the embryonic genome to ensure normal embryonic development
.
During the transition from meiotic I to meiotic II, MARDO disintegrates due to ZAR1 being degraded by the proteasome, which is critical
for the timely degradation of the parent mRNA.

6.
Science: Targeting the intermediator complex kinase module can enhance the anti-tumor efficacy of CAR-T cells

doi:10.
1126/science.
abn5647

T-cell immunotherapy has shown impressive efficacy for some cancers, but most patients do not get a lasting response
.
A central barrier to progress in this type of immunotherapy is the insufficient efficacy of T cells to eradicate the huge tumor burden, which is caused by a variety of factors, including T cell failure, aging, impotence (anergy), and immunosuppression
.
Gene editing has the potential to improve the efficacy of cancer immunotherapy, but it is unclear which genes or groups of genes are most effective at increasing the potency
of T cells when edited.

In a new study, researchers from Stanford University in the United States used genome-wide CRISPR gene knockout screens in human T cells to identify regulators of T cell viability
.
The findings were published in the Nov.
11, 2022 issue of Science as "Enhanced T cell effector activity by targeting the Mediator kinase module.
"

The authors performed two CRISPR screens in human chimeric antigen receptor (CAR) T cells (CAR-T), using a model system to induce T cell dysfunction
by mimicking chronic antigen exposure.
Based on the hypothesis that high proliferation rates and cytokine production rates are the most effective characteristics of anti-tumor T cells, they identified guide RNA (gRNA) rich in T cells that proliferate and produce interleukin-2 (IL-2) and tumor necrosis factor-α (TNFα)
after tumor exposure.

In human T cells, disruption of the mediator complex kinase module is programmed transcriptionally to reconnect effectors
.
Image from Science, 2022, doi:10.
1126/science.
abn5647
.

Both CRISPR screens found genes encoding subunits of the Mediator complex, which are contained in the
intermediator complex kinase module.
Mediator complexes act as bridges between enhancer-bound transcription factors and universal transcription machinery, playing a central role
in establishing cellular identity by coordinating transcription networks.
Targeted culling of MED12 (intermediator complex subunit 12) or CCNC (cyclin C) in human CAR-T cells leads to proliferation, cytokine production, and increased
tumor clearance.
Similar effects
were observed for CAR that targeted multiple tumor antigens and used CD28 or 4-1BB co-stimulation, as well as in T cells expressing engineered T cell receptors (TCRs).
In many model systems, T cells with stemness phenotype and transcriptome characteristics show higher antitumor potency, however, MED12-deficient T cells show weakened stemness and enhanced effector cell phenotype and transcriptome characteristics
.
Consistent with the phenotype of effector cells, MED12-deficient T cells show enhanced metabolic activity and potency, characterized by glycolysis, oxidative phosphorylation, and increased
spare respiratory capacity.
MED12-deficient T cells show sustained potency
after long-term culture and repeated exposure to tumors in vitro and in vivo.
Small molecule-mediated inhibition of catalytic subunit --- of cyclin-dependent kinase modules 8 and 19 (CDK8/19)--- intermediator complex kinase modules likewise increases the proliferation
of healthy unengineered T cells.

To provide a basis for understanding these observations, these authors evaluated changes in chromatin accessibility and modification in
MED12-deficient T cells.
Using chromatin immunoprecipitation sequencing, they confirmed that the intermediator complex kinase module and the intermediator complex core mediaator were essentially colocalized in wild-type CAR-T cells, but the deletion of MED12 increased chromatin occupation
by the intermediator complex core module in more than 800 genomic regions 。 This is consistent with the known interaction of the intermediator complex kinase module in regulating the interaction between the intermediator complex core module and RNA polymerase II (RNAPII), and leads to the hypothesis that the deletion of MED12 or CCNC in T cells selectively reduces the stereoscopic hindrance between the intermediator complex core module and RNAPII, thereby increasing transcription and regulating T cell function
。 Consistent with this, in MED12-deficient CAR-T cells, regions of increased MED1 chromatin occupancy showed increased H3K27 acetylation and were enriched with transcription factors that play a key role in T cell fate--- including enhancers
used by several STAT and AP-1 family members ---.
In MED12-deficient T cells, the most pronounced enhancement observed was STAT5, which manifested as increased
sensitivity to IL-2.
The increased sensitivity of unengineered T cells to IL-2 may also be due to exposure to small molecule CDK8/19 inhibitors
.

7.
Science: Scientists have discovered the key genetic factors that can promote the "immortality" of melanoma

doi:10.
1126/science.
abq0607

Recently, in a study published in the international journal Science entitled "TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma", scientists from the University of Pittsburgh and other institutions revealed the missing piece of the puzzle in the mystery of melanoma controlling its mortality
。 In the article, the researchers describe how they discovered a combination of genetic alterations in tumors to promote their explosive growth and prevent their own death, a finding that may hopefully change the way
oncologists understand and treat melanoma.

About 75% of melanoma contains mutations in the TERT gene that stimulate protein production and increase telomerase activity, however, when scientists prompted TERT mutations in melanocytes, they found that they did not produce the same long telomeres seen in cancer patients' tumors, and it turned out that the mutation in the TERT promoter was only half the
story.
With a background in cancer biology and an interest in telomere research, the researchers decided to look for the missing link
between melanoma, TERT promoter mutations, and long telomeres.
When the researchers combed through the cancer mutation database, they found that a specific region of the telomere-binding protein called TPP1 may be frequently mutated
in melanoma.
The researchers were delighted when they discovered that the mutations in TPP1 were strikingly similar to those in TERT, located in the promoter region of the new annotation of TPP1, and stimulated the production of the protein, which has long been thought to stimulate telomerase activity
.

Biochemists discovered years ago that TPP1 increases telomerase activity in test tubes, but researchers didn't know exactly what would happen
in the clinic.
When the researchers added the mutated TERT and TPP1 back to the cells, the two proteins worked synergistically to produce the unique long telomeres observed in melanoma, the missing factor that scientists have been looking for but has been hidden under
everyone's nose.

This finding may promise to change the way scientists understand the occurrence of melanoma, and may also change current melanoma therapies; By identifying the telomere maintenance system, which is very specific to cancer, scientists have a new target
to develop novel therapies.
In summary, the results show that the TPP1 promoter mutant may be able to cooperate with the activation of TERT, thereby enhancing the telomere maintenance and immortalization characteristics
of melanoma.

8.
Science: Discovered that the RNA-binding protein FMRP allows tumors to evade recognition by the immune system and become resistant to immunotherapy

doi:10.
1126/science.
abl7207

In a new study, researchers from research institutions such as the Swiss Federal Institute of Technology in Lausanne, the University of Bern and the University Hospital of Lausanne have discovered that a protein plays a key role
in helping tumors evade immune destruction.
The RNA-binding protein, named fragile X mental retardation protein (FMRP), regulates a network of genes and cells in the tumor microenvironment, helping to improve its ability to
"evade" immune cells.
Normally, FMRP is involved in regulating protein translation and mRNA stability
in neurons.
But they found that it was abnormally upregulated
in many types of cancer.
The findings were published in the Nov.
18, 2022 issue of Science in the paper "Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.
"

In the new study, the authors used the well-known CRISPR-Cas9 gene-editing technique to knock out the gene that produces FMRP (called FMR1)
in cancer cells caused by mouse pancreas, colon, breast and skin melanocytes.
They then compared
cancer cells that knocked out FMRP to cancer cells that still had the FMR1 gene and therefore expressed the FMRP protein.

FMRP allows tumors to evade attacks
by the immune system.
Image from Science, 2022, doi:10.
1126/science.
abl7207
.

They assessed the survival of mice containing FMRP knockout cancer cells and mice with FMRP-positive wild-type cancer cells, first in mice with compromised immune systems
.
Their comparison showed that the two groups of mice had similar survival rates
.
Remarkably, when they compared the gene-knockout tumors to wild-type tumors grown in mice with functioning immune systems, they found that tumors without FMRP grew more slowly, while they survived longer
.

What this part of the study shows is that FMRP is not involved in stimulating tumor growth itself, but is related
to the adaptive immune system (the part of the immune system that we "train" with vaccines).

Their observations --- wild-type tumors have few invasive T cells, while FMRP knockout tumors are highly inflamed--- further confirming this
.
T cells in tumors knocked out of the FMRP gene caused them to start growing faster and reduced survival in mice, meaning that FMRP was somehow involved in the tumor's evasion
of the immune system.

9.
Science: Novel gene therapies targeting overactive brain cells have the potential to treat neurological disorders

doi:10.
1126/science.
abq6656

In a new study, researchers from University College London in the United Kingdom have developed a new treatment for neurological and psychiatric disorders that works
by reducing the firing of overactive brain cells.
The results of the study were published in the Nov.
4, 2022 issue of Science as "On-demand cell-autonomous gene therapy for brain circuit disorders.
"

Dr Gabriele Lignani, co-corresponding author of the paper from the Queens Square Institute of Neuroscience at University College London, said: "We have invented a new gene therapy that works only by turning on in overactive brain cells and shutting itself down
if they return to normal.
We harnessed the ability of certain DNA sequences to control gene expression in response to metabolic signals
.
By redirecting this active sensing mechanism to drive the production of molecules that prevent brain cells from firing, we found that seizures can be suppressed
.
”

In vitro characterization
of CFOS activity-dependent activation.
Image from Science, 2022, doi:10.
1126/science.
abq6656
.

To develop the new gene therapy, the authors screened several genes known to be activated in response to stimuli and coupled their promoters to potassium channels selected for reducing nerve cell firing
.
This combination of promoter-potassium channels was tested in mice and in miniature brain-like structures (known as brain organoids) cultured in petri dishes, which are made from skin-derived human stem cells
.

They found that the combination of the immediate early gene CFOS promoter and the KCNA1 potassium channel gene was shown to be highly effective in inhibiting neuronal firing after seizure induce, as well as inhibiting spontaneous seizures without any negative effects
on cognitive performance.

The new treatment, which was more effective than gene therapy or anti-epileptic drugs previously tested in the same model, reduced spontaneous seizures in mice with epilepsy by about 80 percent
.
The authors say the new gene therapy could also theoretically be used to treat other diseases in which brain cells are overactive, such as Parkinson's disease
.

10.
Science: New findings are expected to enhance the anti-cancer efficacy of the promising new cancer drug CELMoD

doi:10.
1126/science.
add7574

In a new study, researchers from the Scripps Research Institute in the United States have identified a promising class of new cancer drugs ---CELMoD (CRBN E3 ligase modulatory drug) --- a key feature
needed to be effective 。 The results were published in the Nov.
4, 2022 issue of Science under the title "Molecular glue CELMoD compounds are regulators of cereblon conformation.
"

CELMoDs are designed to attack cancer in a novel way by binding to a regulatory protein called cereblon (CRBN), which then triggers the degradation
of key cancer kinesins.
In the new study, the authors found that in order for this class of drugs to work, they need to cause a key shape change
when combined with CRBNs.
This discovery allows scientists to reliably design effective CELMoD
.

In the new study, first author Randy Watson, Ph.
D.
, a postdoctoral researcher in Lander's lab, spent more than a year designing a formula that stabilizes CRBN when bound to the ubiquitin system partner protein DDB1 in order to image
it with cryo-electron microscopy (cryo-EM).
In this way, he was finally able to resolve the three-dimensional structure
of CRBNs at a near-atomic scale.
Watson also imaged
the complex of CELMoD and target proteins formed with CRBN-DDB1.

CRBN and DDB1∆BPB are open configurations
.
Image from Science, 2022, doi:10.
1126/science.
add7574
.

Their structural data show that CELMoD must bind
to CRBNs in a way that changes its shape or conformation.
They determined that CRBNs had a default "open" conformation, but had to switch to a specific "closed" conformation in order to ubiquitin label
the target protein.

The main implication of this finding is that the pharmaceutical companies that developed CELMoD now have a better understanding
of what their drug candidates must do to be effective.
"Pharmaceutical companies have been developing protein-degrading drugs that bind CRBNs that they think are better degradation drugs, but they don't know it's because these drugs better drive this closed conformation
," Watson said.
So now that they know this, they can test this key property
of their drug.
(Biovalley Bioon.
com)