5VQU

Crystal Structure of HIV-1 Reverse Transcriptase (Y181C) Variant in Complex with N-(6-cyano-3-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-4-methylnaphthalen-1-yl)-2-fluoro-N-methylacetamide (JLJ683), a Non-nucleoside Inhibitor

Summary for 5VQU

• Entry DOI: 10.2210/pdb5vqu/pdb
• Related: 5TER 5VQQ 5VQR 5VQS 5VQT 5VQV 5VQW 5VQX 5VQY 5VQZ
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, N-(6-cyano-3-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}-4-methylnaphthalen-1-yl)-2-fluoro-N-methylacetamide, ... (5 entities in total)
• Functional Keywords: polymerase, reverse transcriptase, hiv, non-nucleoside inhibitor, transferase-hydrolase-inhibitor complex, transferase/hydrolase/inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); More
• Total number of polymer chains: 2
• Total formula weight: 114567.25

Authors

Petrova, Z.O.,Chan, A.H.,Anderson, K.S. (deposition date: 2017-05-09, release date: 2017-08-23, Last modification date: 2023-10-04)

Primary citation

Chan, A.H.,Lee, W.G.,Spasov, K.A.,Cisneros, J.A.,Kudalkar, S.N.,Petrova, Z.O.,Buckingham, A.B.,Anderson, K.S.,Jorgensen, W.L.
Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography.
Proc. Natl. Acad. Sci. U.S.A., 114:9725-9730, 2017

PubMed Abstract: Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.

PubMed: 28827354
DOI: 10.1073/pnas.1711463114

Experimental method

X-RAY DIFFRACTION (2.6 Å)