7EKV

Crystal Structure of human Pin1 complexed with a covalent inhibitor

Summary for 7EKV

• Entry DOI: 10.2210/pdb7ekv/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 8-(2-chloroacetyl)-4-((5-phenylfuran-2-yl)methyl)-1-thia-4,8-diazaspiro[4.5]decan-3-one, 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL, ... (4 entities in total)
• Functional Keywords: covalent, inhibitor, complex, isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 21131.92

Authors

Liu, L.,Li, J. (deposition date: 2021-04-06, release date: 2022-02-16, Last modification date: 2024-11-06)

Primary citation

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.
Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1).
J.Med.Chem., 65:2174-2190, 2022

PubMed Abstract: 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, , that covalently modified Pin1 at Cys113 with an half-maximal inhibitory concentration (IC) of 1.33 ± 0.07 μM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor with an IC of 0.067 ± 0.03 μM. 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 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, effectively inhibited the proliferation and downregulated the Pin1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of Pin1, , which could be an effective probe for studying the functional roles of Pin1.

PubMed: 35089030
DOI: 10.1021/acs.jmedchem.1c01686

Experimental method

X-RAY DIFFRACTION (1.95 Å)