Title

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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2002-05-15

Document Type

Article

Subjects

Binding Sites; Crystallography, X-Ray; Gene Products, gag; HIV Protease; Humans; Hydrogen Bonding; Ligands; Models, Molecular; Molecular Structure; Peptides; Protein Structure, Secondary; *Protein Structure, Tertiary; Substrate Specificity; Water

Disciplines

Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health

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.

Source

Structure. 2002 Mar;10(3):369-81.

Journal/Book/Conference Title

Structure (London, England : 1993)

Related Resources

Link to Article in PubMed

PubMed ID

12005435

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