PDBsum entry 1jlq

Transferase

PDB id: 1jlq

Contents

Protein chains

534 a.a. *

405 a.a. *

Ligands

SBN

* Residue conservation analysis

PDB id:

1jlq

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with 739w94

Structure:

HIV-1 rt, a-chain. Chain: a. Fragment: p66. Engineered: yes. HIV-1 rt, b-chain. Chain: b. Fragment: p51. Engineered: yes

Source:

HIV-1 m:b_hxb2r. Organism_taxid: 11706. Strain: hxb2 isolate. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

3.00Å R-factor: 0.219 R-free: 0.267

Authors:

J.Ren,D.I.Stuart,D.K.Stammers

Key ref:

J.H.Chan et al. (2001). 2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1. J Med Chem, 44, 1866-1882. PubMed id: 11384233 DOI: 10.1021/jm0004906

Date:

16-Jul-01 Release date: 22-Aug-01

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: 534 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: 405 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

DOI no: 10.1021/jm0004906

J Med Chem 44:1866-1882 (2001)

PubMed id: 11384233

2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

J.H.Chan, J.S.Hong, R.N.Hunter, G.F.Orr, J.R.Cowan, D.B.Sherman, S.M.Sparks, B.E.Reitter, C.W.Andrews, R.J.Hazen, M.St Clair, L.R.Boone, R.G.Ferris, K.L.Creech, G.B.Roberts, S.A.Short, K.Weaver, R.J.Ott, J.Ren, A.Hopkins, D.I.Stuart, D.K.Stammers.

ABSTRACT

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.