4X3V
Crystal structure of human ribonucleotide reductase 1 bound to inhibitor
Summary for 4X3V
| Entry DOI | 10.2210/pdb4x3v/pdb |
| Descriptor | 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) |
| Functional Keywords | complex, reducatse, inhibitor, enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 181740.83 |
| Authors | Dealwis, C.G.,Ahmad, M.F.,Alam, I. (deposition date: 2014-12-01, release date: 2015-11-11, Last modification date: 2023-09-27) |
| Primary citation | 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 Cited by 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: 26488902DOI: 10.1021/acs.jmedchem.5b00929 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.7 Å) |
Structure validation
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