8c12

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

spinqualitylabelsall models 8c12, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c12 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.549Å Ligands: SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. 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 Oct 31;42(10):113184. doi: 10.1016/j.celrep.2023.113184. Epub 2023 , Sep 29. PMID:37776520 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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