7KRD

Crystal Structure of HIV-1 Reverse Transcriptase in Complex with 4-(3-chloro-5-cyanophenoxy)-3-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenyl sulfurofluoridate (JLJ702)

Summary for 7KRD

• Entry DOI: 10.2210/pdb7krd/pdb
• Descriptor: HIV-1 REVERSE TRANSCRIPTASE, P66 SUBUNIT, HIV-1 REVERSE TRANSCRIPTASE, P51 SUBUNIT, 4-(3-chloro-5-cyanophenoxy)-3-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenyl sulfurofluoridate (3 entities in total)
• Functional Keywords: polymerase, reverse transcriptase, non-nucleoside inhibitor, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10); More
• Total number of polymer chains: 2
• Total formula weight: 114510.57

Authors

Bertoletti, N.,Ippolito, J.A.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2020-11-19, release date: 2021-01-13, Last modification date: 2024-12-25)

Primary citation

Ippolito, J.A.,Niu, H.,Bertoletti, N.,Carter, Z.J.,Jin, S.,Spasov, K.A.,Cisneros, J.A.,Valhondo, M.,Cutrona, K.J.,Anderson, K.S.,Jorgensen, W.L.
Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.
Acs Med.Chem.Lett., 12:249-255, 2021

PubMed Abstract: Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC values for in vitro inhibition of WT RT and EC values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.

PubMed: 33603971
DOI: 10.1021/acsmedchemlett.0c00612

Experimental method

X-RAY DIFFRACTION (2.7 Å)