7ekv

Crystal Structure of human Pin1 complexed with a covalent inhibitor

spinqualitylabelsall models 7ekv, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Ligands: J50, PE8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The unique proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is reported to activate numerous cancer-driving pathways simultaneously, and aberrant Pin1 activation is present in many human cancers. Here, we identified a novel hit compound, ZL-Pin01, that covalently modified Pin1 at Cys113 with an half-maximal inhibitory concentration (IC50) of 1.33 +/- 0.07 muM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 +/- 0.03 muM. We obtained four co-crystal structures of Pin1 complexed with inhibitors that elucidated the detailed binding mode of the derivatives with Pin1. Interestingly, the co-crystal of Pin1 with ZL-Pin13 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, ZL-Pin13 effectively inhibited the proliferation and downregulated the Pin1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of Pin1, ZL-Pin13, which could be an effective probe for studying the functional roles of Pin1. Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1).,Liu L, Zhu R, Li J, Pei Y, Wang S, Xu P, Wang M, Wen Y, Zhang H, Du D, Ding H, Jiang H, Chen K, Zhou B, Yu L, Luo C J Med Chem. 2022 Feb 10;65(3):2174-2190. doi: 10.1021/acs.jmedchem.1c01686. Epub , 2022 Jan 28. PMID:35089030 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Peptidyl-prolyl cis-trans isomerase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA