PDBsum entry 3dle

Transferase

PDB id: 3dle

Contents

Protein chains

535 a.a. *

403 a.a. *

Ligands

GFA

Waters ×129

* Residue conservation analysis

PDB id:

3dle

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with gf128590.

Structure:

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

Source:

HIV-1 m:b_hxb2r. HIV-1. Organism_taxid: 11706. Strain: hxb2 isolate. Gene: gag-pol. Expressed in: escherichia coli.

Resolution:

2.50Å R-factor: 0.214 R-free: 0.296

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:

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

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 535 a.a.*

Protein chain

P04585  (POL_HV1H2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)

Seq: 1435 a.a.

Struc: 403 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.7.7.- - ?????
• Enzyme class 2: Chains A, B: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: Chains A, B: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 4: Chains A, B: E.C.3.1.-.-
• Enzyme class 5: 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 6: Chains A, B: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: Chains A, B: E.C.3.4.23.16 - HIV-1 retropepsin.
• Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.

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.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

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.