PDBsum entry 3lak

Transferase

PDB id: 3lak

Contents

Protein chains

553 a.a. *

403 a.a. *

Ligands

KR1

SO4 ×4

Metals

_CL

Waters ×207

* Residue conservation analysis

PDB id:

3lak

Name:

Transferase

Title:

Crystal structure of HIV-1 reverse transcriptase in complex with n1- heterocycle pyrimidinedione non-nucleoside inhibitor

Structure:

HIV reverse transcriptase. Chain: a, b. Engineered: yes

Source:

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

Resolution:

2.30Å R-factor: 0.226 R-free: 0.274

Authors:

E.B.Lansdon,M.L.Mitchell

Key ref:

M.L.Mitchell et al. (2010). N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett, 20, 1585-1588. PubMed id: 20137928

Date:

06-Jan-10 Release date: 23-Feb-10

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: 553 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: 403 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

Bioorg Med Chem Lett 20:1585-1588 (2010)

PubMed id: 20137928

N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

M.L.Mitchell, J.C.Son, I.Y.Lee, C.K.Lee, H.S.Kim, H.Guo, J.Wang, J.Hayes, M.Wang, A.Paul, E.B.Lansdon, J.M.Chen, G.Eisenberg, R.Geleziunas, L.Xu, C.U.Kim.

ABSTRACT

A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.