6MK3
Crystallographic solvent mapping analysis of DMSO bound to APE1
Summary for 6MK3
| Entry DOI | 10.2210/pdb6mk3/pdb |
| Descriptor | DNA-(apurinic or apyrimidinic site) lyase, DIMETHYL SULFOXIDE, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | apurinic/apyrimidinic endonuclease, dna repair, abasic site, solvent mapping, lyase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32353.85 |
| Authors | Georgiadis, M.M.,He, H.,Chen, Q. (deposition date: 2018-09-24, release date: 2019-01-30, Last modification date: 2024-03-13) |
| Primary citation | Trilles, R.,Beglov, D.,Chen, Q.,He, H.,Wireman, R.,Reed, A.,Chennamadhavuni, S.,Panek, J.S.,Brown, L.E.,Vajda, S.,Porco Jr., J.A.,Kelley, M.R.,Georgiadis, M.M. Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1. J. Med. Chem., 62:1971-1988, 2019 Cited by PubMed Abstract: Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells. PubMed: 30653918DOI: 10.1021/acs.jmedchem.8b01529 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.478 Å) |
Structure validation
Download full validation report
