High-resolution structure of unbound human immunodeficiency virus 1 subtype C protease: implications of flap dynamics and drug resistance.
The X-ray crystal structure of the unbound state of human immunodeficiency virus 1 (HIV-1) subtype C protease (C PR) has been determined to 1.20 angstroms resolution in the tetragonal space group P4(1)2(1)2, with one monomer per asymmetric unit and unit-cell parameters a = 46.7, c = 100.8 angstroms, allowing full anisotropic least-squares refinement. The refined model has a conventional R factor of 14.1% for all reflections and estimated standard deviations in bond lengths and angles for all main-chain non-H atoms of 0.014 angstroms and 0.030 degrees , respectively. The structure is compared with three unbound subtype B proteases (B PRs) to identify structural changes arising from the naturally occurring polymorphisms and delineate their implications in antiretroviral drug resistance/susceptibility. The unbound C PR exhibits a larger distance between the tips of the flaps, a downward displacement of the 36-41 loop and an increased thermal stability of the 10s loop when compared with the B PR structures. The C PR structure presents the highest resolution of the unbound state of a non-subtype-B PR and adds to the understanding of flap dynamics and drug resistance.
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32603, USA.
Roxana M
RM
Coman
Arthur H
AH
Robbins
Maureen M
MM
Goodenow
Ben M
BM
Dunn
Robert
R
McKenna
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000145:classification; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009038:Motion; D016415:Sequence Alignment
D019380:Anti-HIV Agents; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1