PDBsum entry 4id5

Transferase/transferase inhibitor

PDB id: 4id5

Contents

Protein chains

556 a.a.

412 a.a.

Ligands

T27

DMS ×17

1FF

Metals

_MG

Waters ×889

PDB id:

4id5

Name:

Transferase/transferase inhibitor

Title:

HIV-1 reverse transcriptase with bound fragment at the rnase h primer grip site

Structure:

Reverse transcriptase/ribonuclease h. Chain: a. Fragment: p66 (unp residues 600-1154). Synonym: exoribonuclease h, p66 rt. Engineered: yes. Mutation: yes. P51 rt. Chain: b. Fragment: p51 (unp residues 600-1027).

Source:

Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11678. Strain: bh10. Gene: gag-pol, pol. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.95Å R-factor: 0.188 R-free: 0.209

Authors:

J.D.Bauman,D.Patel,E.Arnold

Key ref:

J.D.Bauman et al. (2013). Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening. J Med Chem, 56, 2738-2746. PubMed id: 23342998 DOI: 10.1021/jm301271j

Date:

11-Dec-12 Release date: 06-Feb-13

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: 556 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: 412 a.a.*

* PDB and UniProt seqs differ at 6 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/jm301271j

J Med Chem 56:2738-2746 (2013)

PubMed id: 23342998

Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening.

J.D.Bauman, D.Patel, C.Dharia, M.W.Fromer, S.Ahmed, Y.Frenkel, R.S.Vijayan, J.T.Eck, W.C.Ho, K.Das, A.J.Shatkin, E.Arnold.

ABSTRACT

HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.