PDBsum entry 3e01

Transferase

PDB id: 3e01

Contents

Protein chains

552 a.a. *

401 a.a. *

Ligands

PZ2

* Residue conservation analysis

PDB id:

3e01

Name:

Transferase

Title:

HIV-rt with non-nucleoside inhibitor annulated pyrazole 2

Structure:

Gag-pol polyprotein. Chain: a. Fragment: unp residues 588-1148. Synonym: pr160gag-pol, reverse transcriptase/ribonuclease h, p66 rt, p51 rt. Engineered: yes. Gag-pol polyprotein. Chain: b. Fragment: unp residues 588-1027.

Source:

Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11706. Gene: gag-pol. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

2.95Å R-factor: 0.235 R-free: 0.279

Authors:

S.F.Harris,A.Villasenor

Key ref:

Z.K.Sweeney et al. (2008). Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase. J Med Chem, 51, 7449-7458. PubMed id: 19007201

Date:

30-Jul-08 Release date: 25-Nov-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: 552 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: 401 a.a.

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 51:7449-7458 (2008)

PubMed id: 19007201

Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase.

Z.K.Sweeney, S.F.Harris, S.F.Arora, H.Javanbakht, Y.Li, J.Fretland, J.P.Davidson, J.R.Billedeau, S.K.Gleason, D.Hirschfeld, J.J.Kennedy-Smith, T.Mirzadegan, R.Roetz, M.Smith, S.Sperry, J.M.Suh, J.Wu, S.Tsing, A.G.Villaseñor, A.Paul, G.Su, G.Heilek, J.Q.Hang, A.S.Zhou, J.A.Jernelius, F.J.Zhang, K.Klumpp.

ABSTRACT

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.