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Mechanism Of Substrate Recognition By Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed By A Novel Structural Intermediate, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Keith Romano, Celia A. Schiffer
Mechanism Of Substrate Recognition By Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variants Revealed By A Novel Structural Intermediate, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Keith Romano, Celia A. Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual "intermediate" conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer …