New protein buildings to assist rational drug design

Inventive rendering of a protein kinase C C1 area (copper), its ligand diacylglycerol (blue), and detergent (cyan). Credit score: Sachin Katti.

In a significant advance for rational drug design, a Texas A&M AgriLife crew has described a number of protein buildings of an important participant in mobile processes. The advance may deliver new concepts for therapies of ailments reminiscent of Alzheimer’s, AIDS, most cancers and others.

Particularly, the work describes the C1 area of protein kinase C, PKC, which helps regulate the protein’s exercise in organisms. Within the buildings, the C1 area wraps round totally different molecules of intense therapeutic curiosity, offering the primary dependable, atomic-resolution information for designing drug candidates.

Printed Could 16 in Nature Communications, the analysis was directed by Tatyana Igumenova, Ph.D., affiliate professor within the Division of Biochemistry and Biophysics within the Texas A&M School of Agriculture and Life Sciences. The venture’s main creator is Sachin Katti, Ph.D., a postdoctoral fellow working with Igumenova.

The examine concerned a collaboration with Inna Krieger, Ph.D., analysis assistant professor, and James Sacchettini, Ph.D., professor, each within the Division of Biochemistry and Biophysics.

Some of the sought-after protein buildings

A wholesome cell responds to chemical indicators in exact, intricate methods. Receiving chemical inputs from the cell’s surroundings and forwarding them to the central management techniques inside the cell nucleus is the duty of specialised proteins reminiscent of PKC.

Improper PKC exercise reveals up in lots of human ailments. In consequence, there may be a lot curiosity find methods to fine-tune PKC exercise with medication. The design of such medication will provide new approaches for treating Alzheimer’s illness, AIDS, most cancers and extra.

“Protein kinase C is likely one of the most intensely studied proteins in cell biology and pharmacology,” Igumenova mentioned. “A serious hurdle has been the dearth of exact structural data to information drug design efforts.”

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One complication for drug design is that the PKC household has 11 members. Completely different PKC members of the family can have reverse physiological results, so a profitable drug candidate should be selective about which PKC it targets.

To try this, drug candidates should match a goal PKC like a key to a lock. However figuring out the 3D construction of a PKC “on-switch”—the C1 area—certain to PKC activators has not been straightforward.

Protein buildings are usually solved utilizing X-ray crystallography. The approach entails utilizing X-rays to find out the place of atoms in a crystal. For this technique, researchers have to create circumstances the place the protein of curiosity crystallizes. But intense efforts in lots of analysis labs over the previous three many years didn’t yield crystals of C1 domains certain to related ligands. Due to this lack of progress, a number of researchers pronounced the duty not possible, Igumenova mentioned.

Crystals of a site of protein kinase C spontaneously shaped in Katti’s NMR pattern tube. Credit score: Sachin Katti.

Fixing a 30-year drawback

Accepting the issue as difficult, Katti and Igumenova determined as an alternative to review the molecules in resolution utilizing nuclear magnetic resonance, NMR, spectroscopy. This concerned discovering the suitable elements to imitate cell membranes, the place the C1 area would encounter ligands.

“Then, one high quality day, Sachin found crystals forming in an previous NMR tube,” Igumenova mentioned. “I give all of the credit score to Sachin, who principally mentioned, ‘I’m going to go and check them and see if they’re really the protein.’ And he was proper. It gave us confidence that crystallization is feasible.”

In flip, Katti offers credence to the insights obtained from NMR, and a little bit of luck.

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“I feel that’s the fantastic thing about doing analysis the place it’s important to use a number of approaches,” he mentioned. “You by no means know when one strategy goes to be helpful for doing one thing with different approaches.”

Insights from NMR and X-ray crystallography

The brand new protein buildings, together with the crew’s NMR outcomes, have already yielded fascinating data. One long-standing thriller has been how C1 domains can accommodate ligands which have very totally different chemical buildings, Igumenova mentioned.

“Our earlier NMR work indicated that the loops of the C1 area that bind ligands are very dynamic,” Igumenova mentioned. “This C1 area is sort of a PAC-man. It binds the membrane, after which it searches for a ligand. As soon as it finds the ligand, it latches on.”

As well as, the construction reveals that the ligand-binding groove has a “water-loving,” or hydrophilic, floor on the backside, and “water-repelling,” or hydrophobic, floor on the high.

“If you consider a lipid molecule, the top group is hydrophilic and the tail is hydrophobic,” Igumenova mentioned. “So, when C1 domains bind lipid ligands, the patterns match.”

The crew’s outcomes embrace the construction of a C1 area certain to its pure ligand, diacylglycerol. As well as, the crew describes a number of different buildings of C1 that embrace totally different compounds of pharmacological curiosity.

The work additionally supplies a way for testing totally different drug candidates, Katti mentioned.

“If you wish to examine fish, you wish to examine them in water,” Katti mentioned. “Now we all know create a membrane-like surroundings the place these very hydrophobic compounds will be examined for C1 binding.”

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Subsequent, Katti and Igumenova plan to discover C1 domains from different PKC members of the family.

“It’s necessary for us to give attention to C1 domains as a result of they’ve inherent variations that may be exploited to realize selectivity,” Igumenova mentioned. “What we’re discovering now’s that not all C1 domains are created equal.”


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Extra data:
Sachin S. Katti et al, Structural anatomy of Protein Kinase C C1 area interactions with diacylglycerol and different agonists, Nature Communications (2022). DOI: 10.1038/s41467-022-30389-2
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