PDBsum entry 6b3c

Viral protein/inhibitor

PDB id: 6b3c

Contents

Protein chains

99 a.a.

Ligands

CKS

Metals

_CL ×3

Waters ×136

PDB id:

6b3c

Name:

Viral protein/inhibitor

Title:

Crystal structure of HIV protease complexed with n-(3-fluoro-2-(2- ((2s,6r)-6-methyl-1-(phenylsulfonyl)piperazin-2-yl)ethyl)phenyl)-3,3- bis(4-fluorophenyl)propanamide

Structure:

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

Source:

Human immunodeficiency virus 1. HIV-1. Organism_taxid: 11676. Gene: gag-pol. Expressed in: human immunodeficiency virus 1. Expression_system_taxid: 11676

Resolution:

1.60Å R-factor: 0.183 R-free: 0.194

Authors:

H.P.Su

Key ref:

C.J.Bungard et al. (2017). Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors. ACS Med Chem Lett, 8, 1292-1297. PubMed id: 29259750

Date:

21-Sep-17 Release date: 03-Jan-18

Protein chains

P04587  (POL_HV1B5) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BH5)

Seq: 1447 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 3 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
• 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
• 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

ACS Med Chem Lett 8:1292-1297 (2017)

PubMed id: 29259750

Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.

C.J.Bungard, P.D.Williams, J.Schulz, C.M.Wiscount, M.K.Holloway, H.M.Loughran, J.J.Manikowski, H.P.Su, D.J.Bennett, L.Chang, X.J.Chu, A.Crespo, M.P.Dwyer, K.Keertikar, G.J.Morriello, A.W.Stamford, S.T.Waddell, B.Zhong, B.Hu, T.Ji, T.L.Diamond, C.Bahnck-Teets, S.S.Carroll, J.F.Fay, X.Min, W.Morris, J.E.Ballard, M.D.Miller, J.A.McCauley.

ABSTRACT

Using the HIV-1 protease binding mode ofMK-8718andPL-100as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative toMK-8718.