PDBsum entry 2ban

Transferase

PDB id: 2ban

Contents

Protein chains

552 a.a. *

427 a.a. *

Ligands

357

Metals

_MN

Waters ×1

* Residue conservation analysis

PDB id:

2ban

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase (rt) in complex with janssen-r157208

Structure:

Reverse transcriptase p66 subunit. Chain: a. Fragment: residues 599-1158. Synonym: HIV-1 rt. Engineered: yes. Mutation: yes. Reverse transcriptase p51 subunit. Chain: b. Fragment: residues 599-1028.

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: bh10 isolate. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: HIV-1 clone 12. Other_details: HIV-1 clone 12

Biol. unit:

Dimer (from PQS)

Resolution:

2.95Å R-factor: 0.243 R-free: 0.305

Authors:

K.Das,E.Arnold

Key ref:

D.M.Himmel et al. (2005). Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. J Med Chem, 48, 7582-7591. PubMed id: 16302798 DOI: 10.1021/jm0500323

Date:

14-Oct-05 Release date: 06-Dec-05

Protein chain

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 a.a.

Struc: 552 a.a.*

Protein chain

P03366  (POL_HV1B1) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH10)

Seq: 1447 a.a.

Struc: 427 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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/jm0500323

J Med Chem 48:7582-7591 (2005)

PubMed id: 16302798

Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains.

D.M.Himmel, K.Das, A.D.Clark, S.H.Hughes, A.Benjahad, S.Oumouch, J.Guillemont, S.Coupa, A.Poncelet, I.Csoka, C.Meyer, K.Andries, C.H.Nguyen, D.S.Grierson, E.Arnold.

ABSTRACT

In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.