4X3V

Crystal structure of human ribonucleotide reductase 1 bound to inhibitor

4X3V の概要

• エントリーDOI: 10.2210/pdb4x3v/pdb
• 分子名称: Ribonucleoside-diphosphate reductase large subunit, THYMIDINE-5'-TRIPHOSPHATE, N~6~-{N-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]-2-methyl-D-alanyl}-D-lysine (3 entities in total)
• 機能のキーワード: complex, reducatse, inhibitor, enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 181740.83

構造登録者

Dealwis, C.G.,Ahmad, M.F.,Alam, I. (登録日: 2014-12-01, 公開日: 2015-11-11, 最終更新日: 2023-09-27)

主引用文献

Ahmad, M.F.,Huff, S.E.,Pink, J.,Alam, I.,Zhang, A.,Perry, K.,Harris, M.E.,Misko, T.,Porwal, S.K.,Oleinick, N.L.,Miyagi, M.,Viswanathan, R.,Dealwis, C.G.
Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators.
J.Med.Chem., 58:9498-9509, 2015

PubMed Abstract: Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.

PubMed: 26488902
DOI: 10.1021/acs.jmedchem.5b00929

実験手法

X-RAY DIFFRACTION (3.7 Å)