Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes.

Abstract

The homodimeric HIV-1 protease is the target of some of the most effective antiviral AIDS therapy, as it facilitates viral maturation by cleaving ten asymmetric and nonhomologous sequences in the Gag and Pol polyproteins. Since the specificity of this enzyme is not easily determined from the sequences of these cleavage sites alone, we solved the crystal structures of complexes of an inactive variant (D25N) of HIV-1 protease with six peptides that correspond to the natural substrate cleavage sites. When the protease binds to its substrate and buries nearly 1000 A2 of surface area, the symmetry of the protease is broken, yet most internal hydrogen bonds and waters are conserved. However, no substrate side chain hydrogen bond is conserved. Specificity of HIV-1 protease appears to be determined by an asymmetric shape rather than a particular amino acid sequence.

• Authors: Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia A Schiffer
• Journal: Structure (London, England : 1993) (Structure) Vol. 10 Issue 3 Pg. 369-81 (Mar 2002) ISSN: 0969-2126 [Print] United States
• PMID: 12005435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Gene Products, gag
• Ligands
• Peptides
• Water
• HIV Protease

Topics

• Binding Sites
• Crystallography, X-Ray
• Gene Products, gag (chemistry, metabolism)
• HIV Protease (chemistry, genetics, metabolism)
• Humans
• Hydrogen Bonding
• Ligands
• Models, Molecular
• Molecular Structure
• Peptides (chemistry, metabolism)
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Substrate Specificity
• Water (chemistry)