Solving a 30-year-old puzzle: Scientists discover new protein structures to help rationally design drugs

In a major advance in rational drug design, a Texas A&M University Agricultural Life team has characterized the structures of several proteins that play a key role in cellular process.

Specifically, this work describes the C1 domain of protein kinase C (PKC), which helps regulate the activity of this protein in the organi.

The research, published May 16 in the journal Nature Communications, was directed by Tatyana Igumenova, PhD, associate professor in the Department of Biochemistry and Biophysics in Texas A&M's College of Agriculture and Life Scienc.

The research was done in collaboration with Research Assistant Professor .

The response of healthy cells to chemical signals is precise and compl.

Inappropriate PKC activity occurs in many human diseas.

"Protein kinase C is one of the most well-studied proteins in cell biology and pharmacology," Igumenova sa.

A complication in drug design is the 11 members of the PKC fami.

To do this, drug candidates must conform to the target PKC, like a key in a lo.

Protein structures are often solved using x-ray crystallograp.

Solving 30 Years of Problems

Katti and Igumenova thought the problem was challenging and decided to use NMR, NMR and spectroscopy to study molecules in soluti.

"Then, on a clear day, Sachin found crystals formed in an old NMR tube," Igumenova sa.

Katie, in turn, believed in the insights gained by MRI, and a little lu.

"I think that's the benefit of doing research, you have to use multiple approaches," he sa.

Insights from NMR and X-ray Crystallography

The new protein structure, along with the team's NMR results, has yielded interesting informati.

"Our previous NMR studies showed that the C1 domain loop that binds ligands is very dynamic," Igumenova sa.

Furthermore, the structure shows that the ligand-binding groove has a "hydrophilic" or hydrophilic surface at the bottom and a "water repellent" or hydrophobic surface at the t.

"If you think about a lipid molecule, the head group is hydrophilic and the tail group is hydrophobic," Igumenova sa.

"So, when the C1 domain binds to the lipid ligand, the patterns mat.

"

The team's results include the structure of the C1 domain bound to the natural ligand, diacylglycer.

In addition, the team also described several other structures of C1, including compounds with different pharmacological implicatio.

The work also provides a way to test different drug candidat.

"If you want to study fish, you should study them in the water," Carty sa.

"Now we know how to create a membrane-like environment where these very hydrophobic compounds can be tested for C1 bindi.

"

Next, Katti and Igumenova plan to explore the C1 domains of other PKC family membe.

"It was important for us to focus on the C1 domains because they have intrinsic differences that can be exploited to achieve selectivity," Igumenova sa.

"We've now found that not all C1 domains are created equ.

"

article title

Structural anatomy of Protein Kinase C C1 domain interactions with diacylglycerol and other agonists