4TYO

PPIase in complex with a non-phosphate small molecule inhibitor.

Summary for 4TYO

• Entry DOI: 10.2210/pdb4tyo/pdb
• Related: 3I6C 3IK8 3IKD 3IKG 3JYJ
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 3-(6-fluoro-1H-benzimidazol-2-yl)-N-(naphthalen-2-ylcarbonyl)-D-alanine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sbdd, ppiase, cell cycle, isomerase, small molecule, nucleus, phosphoprotein, rotamase, peptidyl-prolyl cis-trans isomerase, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q13526
• Total number of polymer chains: 2
• Total formula weight: 28263.32

Authors

Greasley, S.E.,Ferre, R.A. (deposition date: 2014-07-08, release date: 2014-08-20, Last modification date: 2023-12-27)

Primary citation

Guo, C.,Hou, X.,Dong, L.,Marakovits, J.,Greasley, S.,Dagostino, E.,Ferre, R.,Catherine Johnson, M.,Humphries, P.S.,Li, H.,Paderes, G.D.,Piraino, J.,Kraynov, E.,Murray, B.W.
Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket.
Bioorg.Med.Chem.Lett., 24:4187-4191, 2014

PubMed Abstract: The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.

PubMed: 25091930
DOI: 10.1016/j.bmcl.2014.07.044

Experimental method

X-RAY DIFFRACTION (1.75 Å)