PDBsum entry 1t3r

Hydrolase

PDB id: 1t3r

Contents

Protein chains

99 a.a. *

Ligands

PO4 ×5

017

Waters ×261

* Residue conservation analysis

PDB id:

1t3r

Name:

Hydrolase

Title:

HIV protease wild-type in complex with tmc114 inhibitor

Structure:

Protease retropepsin. Chain: a, b. Synonym: HIV-1 protease. Engineered: yes. Mutation: yes. Other_details: complexed with tmc114

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

1.20Å R-factor: 0.140 R-free: 0.179

Authors:

N.M.King,M.Prabu-Jeyabalan,E.A.Nalivaika,P.B.Wigernick,M.P.De Bethune,C.A.Schiffer

Key ref:

D.L.Surleraux et al. (2005). Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem, 48, 1813-1822. PubMed id: 15771427 DOI: 10.1021/jm049560p

Date:

27-Apr-04 Release date: 03-May-05

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 1 residue position (black cross)

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
• 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/jm049560p

J Med Chem 48:1813-1822 (2005)

PubMed id: 15771427

Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.

D.L.Surleraux, A.Tahri, W.G.Verschueren, G.M.Pille, H.A.de Kock, T.H.Jonckers, A.Peeters, S.De Meyer, H.Azijn, R.Pauwels, M.P.de Bethune, N.M.King, M.Prabu-Jeyabalan, C.A.Schiffer, P.B.Wigerinck.

ABSTRACT

The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.