PDBsum entry 6aoc

Transferase / transferase inhibitor

PDB id: 6aoc

Contents

Protein chains

555 a.a.

425 a.a.

Ligands

ZW2 ×2

PGE ×7

EDO ×68

Metals

_MN ×4

Waters ×1147

PDB id:

6aoc

Name:

Transferase / transferase inhibitor

Title:

Crystal structure of an n-hydroxythienopyrimidine-2,4-dione rnase h active site inhibitor with multiple binding modes to HIV reverse transcriptase

Structure:

Reverse transcriptase/ribonuclease h. Chain: a, c. Fragment: p66 domain residues 168-722. Engineered: yes. Mutation: yes. P51 rt. Chain: b, d. Fragment: p51 domain residues 168-595. Synonym: exoribonuclease h, p66 rt.

Source:

Human immunodeficiency virus type 1 group m subtype b (isolate bh10). HIV-1. Organism_taxid: 11678. Strain: isolate bh10. Gene: gag-pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.80Å R-factor: 0.188 R-free: 0.226

Authors:

K.A.Kirby,S.G.Sarafianos

Key ref:

J.Kankanala et al. (2017). Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H. Eur J Med Chem, 141, 149-161. PubMed id: 29031062

Date:

15-Aug-17 Release date: 08-Aug-18

Protein chains

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

Seq: 1447 a.a.

Struc: 555 a.a.*

Protein chains

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

Seq: 1447 a.a.

Struc: 425 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B, C, D: E.C.2.7.7.- - ?????
• Enzyme class 2: Chains A, B, C, D: 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, C, D: 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, C, D: E.C.3.1.-.-
• Enzyme class 5: Chains A, B, C, D: 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, C, D: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: Chains A, B, C, D: 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

Eur J Med Chem 141:149-161 (2017)

PubMed id: 29031062

Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H.

J.Kankanala, K.A.Kirby, A.D.Huber, M.C.Casey, D.J.Wilson, S.G.Sarafianos, Z.Wang.

ABSTRACT

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC₅₀ = 0.04 μM) with decent antiviral potency (EC₅₀ = 7.4 μM) and no cytotoxicity (CC₅₀ > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC₅₀ = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.