PDBsum entry 1d4l

Hydrolase

PDB id: 1d4l

Contents

Protein chains

99 a.a. *

Ligands

SO4 ×3

PI9

Waters ×121

* Residue conservation analysis

PDB id:

1d4l

Name:

Hydrolase

Title:

HIV-1 protease complexed with a macrocyclic peptidomimetic inhibitor

Structure:

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

Source:

Synthetic: yes. Other_details: sf2 isolate, chemically synthesised protein corresponds to the protease from HIV-1, with 4 mutations per monomer

Biol. unit:

Dimer (from PQS)

Resolution:

1.75Å R-factor: 0.189 R-free: 0.231

Authors:

J.D.Tyndall,R.C.Reid,D.P.Tyssen,D.K.Jardine,B.Todd,M.Passmore, D.R.March,L.K.Pattenden,D.Alewood,S.H.Hu,P.F.Alewood,C.J.Birch, J.L.Martin,D.P.Fairlie

Key ref:

J.D.Tyndall et al. (2000). Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. J Med Chem, 43, 3495-3504. PubMed id: 11000004 DOI: 10.1021/jm000013n

Date:

04-Oct-99 Release date: 11-Oct-00

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 4 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

DOI no: 10.1021/jm000013n

J Med Chem 43:3495-3504 (2000)

PubMed id: 11000004

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

J.D.Tyndall, R.C.Reid, D.P.Tyssen, D.K.Jardine, B.Todd, M.Passmore, D.R.March, L.K.Pattenden, D.A.Bergman, D.Alewood, S.H.Hu, P.F.Alewood, C.J.Birch, J.L.Martin, D.P.Fairlie.

ABSTRACT

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.