5FDL
Crystal Structure of K103N/Y181C Mutant HIV-1 Reverse Transcriptase (RT) in Complex with IDX899
Summary for 5FDL
| Entry DOI | 10.2210/pdb5fdl/pdb |
| Descriptor | P51 Reverse transcriptase, P66 Reverse transcriptase, methyl (R)-(2-carbamoyl-5-chloro-1H-indol-3-yl)[3-(2-cyanoethyl)-5-methylphenyl]phosphinate (3 entities in total) |
| Functional Keywords | hiv-1 reverse transcriptase, phosphoindole, nnrti, mutation, hydrolase |
| Biological source | Human immunodeficiency virus 1 (HIV-1) More |
| Cellular location | Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366 |
| Total number of polymer chains | 2 |
| Total formula weight | 115798.16 |
| Authors | Dousson, C.B.,Alexandre, F.-R.,Convard, T.,Fisher, M.,Lamers, M.B.A.C.,Leonard, P.M. (deposition date: 2015-12-16, release date: 2016-02-17, Last modification date: 2024-01-10) |
| Primary citation | Dousson, C.,Alexandre, F.R.,Amador, A.,Bonaric, S.,Bot, S.,Caillet, C.,Convard, T.,da Costa, D.,Lioure, M.P.,Roland, A.,Rosinovsky, E.,Maldonado, S.,Parsy, C.,Trochet, C.,Storer, R.,Stewart, A.,Wang, J.,Mayes, B.A.,Musiu, C.,Poddesu, B.,Vargiu, L.,Liuzzi, M.,Moussa, A.,Jakubik, J.,Hubbard, L.,Seifer, M.,Standring, D. Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor. J.Med.Chem., 59:1891-1898, 2016 Cited by PubMed Abstract: Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant. PubMed: 26804933DOI: 10.1021/acs.jmedchem.5b01430 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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