8c12 | pdb_00008c12
Identification of an intermediate activation state of PAK5 reveals a novel mechanism of kinase inhibition.
Structural highlights
FunctionPAK5_HUMAN Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates the proto-oncogene RAF1 and stimulates its kinase activity. Promotes cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Phosphorylates CTNND1, probably to regulate cytoskeletal organization and cell morphology. Keeps microtubules stable through MARK2 inhibition and destabilizes the F-actin network leading to the disappearance of stress fibers and focal adhesions.[1] [2] [3] [4] [5] Publication Abstract from PubMedKinases 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. Affimer-mediated locking of p21-activated kinase 5 in an intermediate activation state results in kinase inhibition.,Martin HL, Turner AL, Higgins J, Tang AA, Tiede C, Taylor T, Siripanthong S, Adams TL, Manfield IW, Bell SM, Morrison EE, Bond J, Trinh CH, Hurst CD, Knowles MA, Bayliss RW, Tomlinson DC Cell Rep. 2023 Sep 29;42(10):113184. doi: 10.1016/j.celrep.2023.113184. PMID:37776520[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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