8C12

Identification of an intermediate activation state of PAK5 reveals a novel mechanism of kinase inhibition.

This is a non-PDB format compatible entry.

Summary for 8C12

• Entry DOI: 10.2210/pdb8c12/pdb
• Descriptor: Serine/threonine-protein kinase PAK 5, PAK5-Af17 (3 entities in total)
• Functional Keywords: kinase, pak5, affimer, urothelial cancer., transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 46055.12

Authors

Martin, H.L.,Turner, A.L.,Trinh, C.H.,Bayliss, R.W.,Tomlinson, D.C. (deposition date: 2022-12-19, release date: 2023-10-25, Last modification date: 2024-10-16)

Primary citation

Martin, H.L.,Turner, A.L.,Higgins, J.,Tang, A.A.,Tiede, C.,Taylor, T.,Siripanthong, S.,Adams, T.L.,Manfield, I.W.,Bell, S.M.,Morrison, E.E.,Bond, J.,Trinh, C.H.,Hurst, C.D.,Knowles, M.A.,Bayliss, R.W.,Tomlinson, D.C.
Affimer-mediated locking of p21-activated kinase 5 in an intermediate activation state results in kinase inhibition.
Cell Rep, 42:113184-113184, 2023

PubMed Abstract: Kinases are important therapeutic targets, and their inhibitors are classified according to their mechanism of action, which range from blocking ATP binding to covalent inhibition. Here, a mechanism of inhibition is highlighted by capturing p21-activated kinase 5 (PAK5) in an intermediate state of activation using an Affimer reagent that binds in the P+1 pocket. PAK5 was identified from a non-hypothesis-driven high-content imaging RNAi screen in urothelial cancer cells. Silencing of PAK5 resulted in reduced cell number, G1/S arrest, and enlargement of cells, suggesting it to be important in urothelial cancer cell line survival and proliferation. Affimer reagents were isolated to identify mechanisms of inhibition. The Affimer PAK5-Af17 recapitulated the phenotype seen with siRNA. Co-crystallization revealed that PAK5-Af17 bound in the P+1 pocket of PAK5, locking the kinase into a partial activation state. This mechanism of inhibition indicates that another class of kinase inhibitors is possible.

PubMed: 37776520
DOI: 10.1016/j.celrep.2023.113184

Experimental method

X-RAY DIFFRACTION (1.549 Å)