6DUN

Crystal Structure Analysis of PIN1

Summary for 6DUN

• Entry DOI: 10.2210/pdb6dun/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, TRIHYDROXYARSENITE(III) (3 entities in total)
• Functional Keywords: prolyl isomerase, isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 27462.18

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2018-06-21, release date: 2019-03-06, Last modification date: 2023-10-11)

Primary citation

Kozono, S.,Lin, Y.M.,Seo, H.S.,Pinch, B.,Lian, X.,Qiu, C.,Herbert, M.K.,Chen, C.H.,Tan, L.,Gao, Z.J.,Massefski, W.,Doctor, Z.M.,Jackson, B.P.,Chen, Y.,Dhe-Paganon, S.,Lu, K.P.,Zhou, X.Z.
Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells.
Nat Commun, 9:3069-3069, 2018

PubMed Abstract: Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

PubMed: 30093655
DOI: 10.1038/s41467-018-05402-2

Experimental method

X-RAY DIFFRACTION (1.59 Å)