Two new X-ray structures of an HIV-1 protease mutant (A71V, V82T, I84V) in complex with inhibitors SE and SQ, pseudotetrapeptide inhibitors with an acyclic S-hydroxyethylamine isostere, were determined. Comparison of eight structures exploring the binding of four similar inhibitors--SE, SQ (S-hydroxyethylamine isostere), OE (ethyleneamine), and QF34 (hydroxyethylene)--to wild-type and A71V/V82T/I84V HIV-1 protease elucidates the principles of altered interaction with changing conditions. The A71V mutation, which is distant from the active site, causes changes in the structure of the enzyme detectable by the means of X-ray structure analysis, and a route of propagation of the effect toward the active site is proposed.
- MeSH
- ethanolamin chemie MeSH
- financování organizované MeSH
- HIV-proteasa genetika chemie MeSH
- inhibitory HIV-proteasy chemie MeSH
- krystalografie rentgenová MeSH
- ligandy MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- mutace MeSH
- oligopeptidy chemie MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
Peptidomimetic inhibitors of human immunodeficiency virus-1 protease are successful lead substances for the development of virostatic drugs against HIV as the causative agent of acquired immunodeficiency syndrome (AIDS). The hydroxyethylamine isostere of the proteolytic cleavage intermediate provides a suitable replacement for the peptide bond. A series of acyclic pseudopeptide inhibitors with the hydroxyethylamine isostere varying in chiral carbon configuration and P'2 residue type were structurally analysed by single-crystal X-ray crystallography. The compounds inhibit HIV protease with subnanomolar inhibition constants and block viral replication in tissue cultures. Here, the structure of such a complex with the R configuration of the isosteric group (PDB code 1zsf) is presented together with newly available synchrotron data for a complex with the S stereoisomer of the inhibitor (PDB code 1zsr). Comparison of the structure and binding with other complexes of HIV-1 protease and similar inhibitors contributes to the understanding of how these molecules bind to the wild-type form of this enzyme. The hydroxy group of the R stereoisomer interacts with one of the catalytic aspartic acids by a short hydrogen bond with rather extreme geometry. The change of configuration of the chiral carbon bearing the hydroxyl from S to R does not influence the inhibition efficiency in this case.
- MeSH
- ethanolaminy chemie MeSH
- financování organizované MeSH
- HIV-1 enzymologie MeSH
- HIV-proteasa chemie metabolismus MeSH
- inhibitory HIV-proteasy chemie MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- oligopeptidy chemie MeSH
- stereoizomerie MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
The specificity of the proteinase of myeloblastosis-associated virus (MAV) was studied with (a) 21 substrate-based inhibitors, (b) 9 inhibitors with pseudopalindrome sequences, (c) 8 chimeric inhibitors, and (d) 3 compounds designed as human immunodeficiency virus 1 (HIV-1) proteinase inhibitors. The central inhibitory unit (transition state or cleaved bond analog) and the role of the inhibitor side chains from P4 to P4' were investigated. MAV proteinase prefers an aromatic side chain in P1 and a small aliphatic nonpolar chain in P2 and P2'. Residues in P5 and P4 positions are outside of the short catalytic cleft of the enzyme, but still influence binding considerably. The data obtained provide evidence that the MAV proteinase has generally lower specificity and poorer binding than the HIV proteinase.
- MeSH
- aspartátové endopeptidasy * antagonisté a inhibitory MeSH
- HIV-1 enzymologie MeSH
- HIV-proteasa metabolismus MeSH
- inhibitory proteas farmakologie chemická syntéza MeSH
- kinetika MeSH
- molekulární sekvence - údaje MeSH
- oligopeptidy farmakologie chemická syntéza MeSH
- sekvence aminokyselin MeSH
- substrátová specifita MeSH
- virus ptačí myeloblastózy * enzymologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- srovnávací studie MeSH
