6VAJ
Crystal Structure Analysis of human PIN1
Summary for 6VAJ
| Entry DOI | 10.2210/pdb6vaj/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 2-chloro-N-(2,2-dimethylpropyl)-N-[(3R)-1,1-dioxo-1lambda~6~-thiolan-3-yl]acetamide, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | ppiase, covalent inhibitor, isomerase, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20512.18 |
| Authors | Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2019-12-17, release date: 2020-12-30, Last modification date: 2024-10-23) |
| Primary citation | Dubiella, C.,Pinch, B.J.,Koikawa, K.,Zaidman, D.,Poon, E.,Manz, T.D.,Nabet, B.,He, S.,Resnick, E.,Rogel, A.,Langer, E.M.,Daniel, C.J.,Seo, H.S.,Chen, Y.,Adelmant, G.,Sharifzadeh, S.,Ficarro, S.B.,Jamin, Y.,Martins da Costa, B.,Zimmerman, M.W.,Lian, X.,Kibe, S.,Kozono, S.,Doctor, Z.M.,Browne, C.M.,Yang, A.,Stoler-Barak, L.,Shah, R.B.,Vangos, N.E.,Geffken, E.A.,Oren, R.,Koide, E.,Sidi, S.,Shulman, Z.,Wang, C.,Marto, J.A.,Dhe-Paganon, S.,Look, T.,Zhou, X.Z.,Lu, K.P.,Sears, R.C.,Chesler, L.,Gray, N.S.,London, N. Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nat.Chem.Biol., 17:954-963, 2021 Cited by PubMed Abstract: The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target. PubMed: 33972797DOI: 10.1038/s41589-021-00786-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.42 Å) |
Structure validation
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