PDBsum entry 1tkt

Transferase

PDB id: 1tkt

Contents

Protein chains

516 a.a. *

399 a.a. *

Ligands

PO4 ×3

H12

Metals

_MG

Waters ×37

* Residue conservation analysis

PDB id:

1tkt

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with gw426318

Structure:

Pol polyproteins [reverse transcriptase], chain a. Chain: a. Fragment: p66. Engineered: yes. Pol polyproteins [reverse transcriptase], chain b. Chain: b. Fragment: p51. Engineered: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: hxb2 isolate. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

2.60Å R-factor: 0.208 R-free: 0.282

Authors:

A.L.Hopkins,J.Ren,D.I.Stuart,D.K.Stammers

Key ref:

A.L.Hopkins et al. (2004). Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1. J Med Chem, 47, 5912-5922. PubMed id: 15537346 DOI: 10.1021/jm040071z

Date:

09-Jun-04 Release date: 07-Dec-04

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: 516 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: 399 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

DNA(n) + 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) (Bound ligand (Het Group name = PO4) matches with 55.56% similarity) + 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/jm040071z

J Med Chem 47:5912-5922 (2004)

PubMed id: 15537346

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1.

A.L.Hopkins, J.Ren, J.Milton, R.J.Hazen, J.H.Chan, D.I.Stuart, D.K.Stammers.

ABSTRACT

We have used a structure-based approach to design a novel series of non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Detailed analysis of a wide range of crystal structures of HIV-1 RT-NNRTI complexes together with data on drug resistance mutations has identified factors important for tight binding of inhibitors and resilience to mutations. Using this approach we have designed and synthesized a novel series of quinolone NNRTIs. Crystal structure analysis of four of these compounds in complexes with HIV-1 RT confirms the predicted binding modes. Members of this quinolone series retain high activity against the important resistance mutations in RT at Tyr181Cys and Leu100Ile.