4RW6

Crystal Structure of HIV-1 Reverse Transcriptase (Y181C) variant in complex with (E)-3-(3-chloro-5-(4-chloro-2-(2-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)phenyl)acrylonitrile (JLJ494), a Non-nucleoside Inhibitor

Summary for 4RW6

• Entry DOI: 10.2210/pdb4rw6/pdb
• Related: 1JKH 1JLA 1JLC 3BGR 4H4M 4I2Q 4LSL 4MFB 4RW4 4RW7 4RW8 4RW9
• Descriptor: Reverse transcriptase/ribonuclease H, p66 subunit, Reverse transcriptase/ribonuclease H, p51 subunit, (2E)-3-(3-chloro-5-{4-chloro-2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}phenyl)prop-2-enenitrile, ... (4 entities in total)
• Functional Keywords: polymerase, transferase, hydrolase, rnaseh, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 BH10 (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: 114412.96

Authors

Frey, K.M.,Anderson, K.S. (deposition date: 2014-12-01, release date: 2015-04-29, Last modification date: 2023-09-20)

Primary citation

Frey, K.M.,Puleo, D.E.,Spasov, K.A.,Bollini, M.,Jorgensen, W.L.,Anderson, K.S.
Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants.
J.Med.Chem., 58:2737-2745, 2015

PubMed Abstract: The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomolar activity against HIV strains with wild-type RT but lose potency against variants with single Y181C and double K103N/Y181C mutations. As guided by structure-based and computational studies, removal of the 5-Cl substitution of compound 1 on the catechol aryl ring system led to a new analogue compound 2 that maintains greater potency against Y181C and K103N/Y181C variants and better solubility (510 μg/mL). Crystal structures were determined for wild-type, Y181C, and K103N/Y181C RT in complex with both compounds 1 and 2 to understand the structural basis for these findings. Comparison of the structures reveals that the Y181C mutation destabilizes the binding mode of compound 1 and disrupts the interactions with residues in the pocket. Compound 2 maintains the same conformation in wild-type and mutant structures, in addition to several interactions with the NNRTI binding pocket. Comparison of the six crystal structures will assist in the understanding of compound binding modes and future optimization of the catechol diether series.

PubMed: 25700160
DOI: 10.1021/jm501908a

Experimental method

X-RAY DIFFRACTION (2.631 Å)