PDBsum entry 3o9h

Hydrolase/hydrolase inhibitor

PDB id: 3o9h

Contents

Protein chains

99 a.a.

Ligands

PO4 ×4

ACT

K2E

Waters ×156

PDB id:

3o9h

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of wild-type HIV-1 protease in complex with kd26

Structure:

Protease. Chain: a, b. Fragment: HIV-1 protease. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. HIV-1. Organism_taxid: 11676. Strain: hxb2. Gene: gag-pol, pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.70Å R-factor: 0.168 R-free: 0.208

Authors:

C.A.Schiffer,M.N.L.Nalam

Key ref:

M.N.Nalam et al. (2013). Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem Biol, 20, 1116-1124. PubMed id: 24012370 DOI: 10.1016/j.chembiol.2013.07.014

Date:

04-Aug-10 Release date: 10-Aug-11

Protein chains

P03369  (POL_HV1A2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2)

Seq: 1437 a.a.

Struc: 99 a.a.*

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

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.- - ?????
• Enzyme class 2: E.C.2.7.7.49 - RNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

DNA(n) + 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) (Bound ligand (Het Group name = PO4) matches with 55.56% similarity) + diphosphate

• Enzyme class 3: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate

DNA(n) + 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) (Bound ligand (Het Group name = PO4) matches with 55.56% similarity) + diphosphate

• Enzyme class 4: E.C.3.1.-.-
• Enzyme class 5: 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: E.C.3.1.26.13 - retroviral ribonuclease H.
• Enzyme class 7: 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: 10.1016/j.chembiol.2013.07.014

Chem Biol 20:1116-1124 (2013)

PubMed id: 24012370

Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance.

M.N.Nalam, A.Ali, G.S.Reddy, H.Cao, S.G.Anjum, M.D.Altman, N.K.Yilmaz, B.Tidor, T.M.Rana, C.A.Schiffer.

ABSTRACT

The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against different clades of HIV as well as a panel of 12 drug-resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.