Cell: Continuous progress! Yigong Shi's team uncovered the whole process of combining Alzheimer's important protein gamma secretase with drugs for the first time

γ of GSI and regulators provides attractive treatment opportunities for Alzheimer's disease (AD) and cancer.
, how these GSI and GSMs target γ-secretion enzymes is still largely unknown.
December 28, 2020, a team from Tsinghua University published a research paper entitled "Structural basis of γ-secretaseion and modulation by small γ drugs" online, which looked at the structural mechanisms of three different GSI inhibitors γ secretion enzymes: S. Sgacestat, Avagacestat, and L685,458.
the study also reported the atomic structure of γ-secretion enzymes in combination with GSM E2012, with an overall resolution of 2.6 to 3.1 .
note that each GSI occupies the same general position on presenilin1 (PS1) to accommodate amyloid preloom proteins or Notch β chains, thus interfering with substrate collection.
L685,458 directly coordinates the two catalytic winter acid residues of PS1.
E2012 in combination with the γ-secretion enzyme on the outside of the cell may explain its regulatory activity.
In summary, the study revealed the workings of three different γ-secretase inhibitors, analyzed their commonalities and, more importantly, revealed the differences between the three, and laid a solid foundation for future optimization and design of inhibitors with substrate specificity.
This study sheds more light on how these regulators and inhibitors inhibit substrate entry, providing an explanation for previous clinical drug failures, and will greatly advance the design and optimization of next-generation γ-secretase inhibitors and regulators.
addition, on November 27, 2020, West Lake Laboratory (a provincial laboratory approved by the Zhejiang provincial government, relying on West Lake University), West Lake University, Tsinghua University and other multi-unit cooperation, Shi Igong and Wan Yu Xue joint newsletter published in Science Online entitled "Mechanism of spliceosome remodel" By the atPase/helicase Prp2 and its coactivator Spp2" research paper, the study of Prp2, the total activation factor Spp2 composite Prp2 and loaded With Prp2 activation shear atomic structure, as well as structural guidance of the results of bio-chemical analysis.
Prp2 binds to the shear body weakly, it does not function without Sp2, which binds steadily to the anchor molecules on Prp2 and the shear body, binding Prp2 to the active shear and allowing Prp2 to function.
Pre-mRNA is loaded into the characteristic channel between the N-and C-half of Prp2, where N-half's Leu536 and C-half's Arr844 prevent pre-mRNA from sliding backward to its 5' end.
between domains in ATP binding and hydrolysing trigger Prp2, driving the pre-mRNA to move one-way toward its 3' end.
these conservative mechanisms explain the coupling of the shear reshaping to the Pre-mRNA scissors.
May 6, 2020, Shi's team (Tsinghua University is the first unit) published an online post on Cell Research entitled "Structure of the cytoplasmic ring of the Xenopus laevis nuclear pore complex by cryo-electron micros" A research paper by copy single particle analysiss, which introduces the single-particle cryo-EM structure of the African pawn NPC CR, with an average resolution of 5.5-7.9-7.9-gram and a local resolution of 4.5.
improved resolution allows secondary structure elements to be identified and placed in most CR components.
two Y compounds in each CR sub-base interact with each other and bond with the Y-composite of the flank sub-base to form a circular bracket.
in each CR sub-base, the area containing Nup358 is encased in the stems of two Y compounds, which may stabilize the stent.
the short arms of the two Y-mates to the Nup205 and to the stems of the adjacent Y-mates.
area containing the Nup214 connects the two Y-couples with an extended curling spiral and protrudes into the axial hole of the NPC.
these previously unsealed structural features reveal an understanding of NPC assembly (click to read).
May 4, 2020, Shi's team (the first unit at Westlake University) published a research paper online on Cell Research entitled "Molecular architecture of the luminal ring of the Xenopus laevis nuclear pore complex", which looked at the frozen electron fault scanning (cryo-ET) structure of the NPC cavity ring (LR) of African claw oocytes.
structural features observed by LR can be independently identified by single-particle cryogenic electron microscope (cryo-EM) analysis.
the study sheds light on previously unknown features of LR and may explain npc elasticity (click to read).
-secretion enzymes γ membrane-encumvirins cut the cross-membrane domain (TM) of multiple signal proteins, such as amyloid prelosor proteins (APP) and Notch.
app is first cut by a secretion-secretion enzyme β extracellular space.
the 99-bit residual fragment (APP-C99) of the C end obtained by γ-secretase is further proteolysis to produce in-cell domain (AICD) and 48-bit or 49-bit residual transmeanine peptides (A beta 48 or A beta 49).
then, A-beta 48 and A-beta-49 are modified with γ-secretion enzymes for every three or four residuals, resulting in different lengths of A-beta peptides and various by-products of tripeptides and four peptides.
accumulation of A-beta peptides β the formation of plaque-amyloid plaques, a hallmark of Alzheimer's disease (AD).
γ-secretase consists of four sub-base: catalytic sub-base PS1 or PS2, Pen-2, APH-1, and Nicastrin (NCT).
majority of familial AD-derived (FAD) mutations target PS1, while PS2 and APP play a smaller role.
almost all mutations can lead to protein hydrolysaling abnormalities in app.
these observations present the amyloid hypothesis, which suggests that A-beta glomeration and plaque deposition are pathogenic factors in AD development.
hypothesis predicts that inhibiting γ-secretase may reduce AD production and reduce the accumulation of A-beta oligomers and plaque deposits, which may be an effective treatment for AD.
Semagacestat, developed by Eli Lily and code-named LY-450139, is the first γ-secretase inhibitor (GSI) to enter Phase III clinical evaluation.
, contrary to encouraging early results, Semagacestat failed to show cognitive improvement in Phase III, but had serious side effects.
side effects are attributed to cleavage inhibition of other substrates such as Notch.
to address this problem, a substrate-specific GSI has been developed, and the representative clinical candidate drug Avagacestat (called BMS-708163) is preferred to Notch in suppressing app cleavage.
, high doses of Avagacestat can still inhibit Notch cracking and show toxicity.
GSI is divided into transitional state similars (TSA) and non-TSA according to the suppression mechanism.
Semagacestat and Avagacestat are non-competitive non-TSA inhibitors.
, the small molecule L685,458 is widely studied as a competitive TSA.
L685,458 directly binds to the active bits of PS1.
addition to GSI, γ-secretion enzyme regulator (GSM) is also considered an attractive class of small molecules to relieve AD symptoms.
GSM may promote further cutting of A-beta 42, thereby reducing the amount of A-beta peptides that are easy to aggregate.
GSI, GSM is identified at different γ locations away from the active points of the ocrins-secretion enzyme.
, specific GSI can be used in conjunction with GSM for substrate selective inhibition.
small molecule E2012 is a well-used classic member of the hybrid GSM family.
the development of more specific GSI needs to understand the general inhibition and the rationale of substrate selective inhibition.
improvement of GSM requires information about the structure γ identified by the enzyme-secretion enzyme.
, this information is still largely unknown.
so far, there is no γ atomic model for identifying any GSI or GSM by using a secretion-secretase.
study, three different structural mechanisms of GSI γ inhibition of secretion enzymes were reported: Semagacestat, Avagacestat, and L685,458.
the study also reported the atomic structure of γ-secretion enzymes in combination with GSM E2012, with an overall resolution of 2.6 to 3.1 .
note that each GSI occupies the same general position on presenilin1 (PS1) to accommodate amyloid preloom proteins or Notch β chains, thus interfering with substrate collection.
L685,458 directly coordinates the two catalytic winter acid residues of PS1.
E2012 in combination with the γ-secretion enzyme on the outside of the cell may explain its regulatory activity.
In summary, the study revealed the workings of three different γ-secretase inhibitors, analyzed their commonalities and, more importantly, revealed the differences between the three, and laid a solid foundation for future optimization and design of inhibitors with substrate specificity.
This study sheds more light on how these regulators and inhibitors inhibit substrate entry, providing an explanation for previous clinical drug failures, and will greatly advance the design and optimization of next-generation γ-secretase inhibitors and regulators.
It is understood that Shi Yigong is the co-author of the research paper, Yang Guangguang (Professor of China Agricultural University), Zhou Rui (Assistant Professor, School of Life, Tsinghua University), and Guo Xuefei (Ph.D. Student, School of Life, Tsinghua University) as co-authors of the paper.