PDBsum entry 3dm2

Transferase

PDB id: 3dm2

Contents

Protein chains

532 a.a. *

400 a.a. *

Ligands

PO4 ×2

GWE

* Residue conservation analysis

PDB id:

3dm2

Name:

Transferase

Title:

Crystal structure of HIV-1 k103n mutant reverse transcriptase in complex with gw564511.

Structure:

Reverse transcriptase/ribonuclease h. Chain: a. Fragment: gag-pol polyprotein p66 subunit. Synonym: p66 rt. Engineered: yes. Mutation: yes. P51 rt. Chain: b. Fragment: gag-pol polyprotein p51 subunit.

Source:

Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11706. Strain: hxb2 isolate. Gene: gag-pol. Expressed in: escherichia coli.

Resolution:

3.10Å R-factor: 0.222 R-free: 0.307

Authors:

J.Ren,P.P.Chamberlain,D.K.Stammers

Key ref:

J.Ren et al. (2008). Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors. J Med Chem, 51, 5000-5008. PubMed id: 18665583

Date:

30-Jun-08 Release date: 12-Aug-08

Protein chain

A7YKL0  (A7YKL0_HV1) -  Pol protein (Fragment) from Human immunodeficiency virus type 1

Seq: 1008 a.a.

Struc: 532 a.a.*

Protein chain

Q74596  (Q74596_HV1) -  Pol (Fragment) from Human immunodeficiency virus type 1

Seq: 1015 a.a.

Struc: 400 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.3.1.13.2 - exoribonuclease H.
• Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
• Enzyme class 2: Chains A, B: E.C.3.1.26.13 - retroviral ribonuclease H.

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

J Med Chem 51:5000-5008 (2008)

PubMed id: 18665583

Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors.

J.Ren, P.P.Chamberlain, A.Stamp, S.A.Short, K.L.Weaver, K.R.Romines, R.Hazen, A.Freeman, R.G.Ferris, C.W.Andrews, L.Boone, J.H.Chan, D.K.Stammers.

ABSTRACT

Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.