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Structural Basis For Coevolution Of A Human Immunodeficiency Virus Type 1 Nucleocapsid-P1 Cleavage Site With A V82a Drug-Resistant Mutation In Viral Protease, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Structural Basis For Coevolution Of A Human Immunodeficiency Virus Type 1 Nucleocapsid-P1 Cleavage Site With A V82a Drug-Resistant Mutation In Viral Protease, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Celia A. Schiffer
Maturation of human immunodeficiency virus (HIV) depends on the processing of Gag and Pol polyproteins by the viral protease, making this enzyme a prime target for anti-HIV therapy. Among the protease substrates, the nucleocapsid-p1 (NC-p1) sequence is the least homologous, and its cleavage is the rate-determining step in viral maturation. In the other substrates of HIV-1 protease, P1 is usually either a hydrophobic or an aromatic residue, and P2 is usually a branched residue. NC-p1, however, contains Asn at P1 and Ala at P2. In response to the V82A drug-resistant protease mutation, the P2 alanine of NC-p1 mutates to valine …
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 …
Structural And Thermodynamic Basis For The Binding Of Tmc114, A Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Piet Wigerinck, Marie-Pierre De Bethune, Celia Schiffer
Structural And Thermodynamic Basis For The Binding Of Tmc114, A Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor, Nancy King, Moses Prabu-Jeyabalan, Ellen Nalivaika, Piet Wigerinck, Marie-Pierre De Bethune, Celia Schiffer
Celia A. Schiffer
TMC114, a newly designed human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is extremely potent against both wild-type (wt) and multidrug-resistant (MDR) viruses in vitro as well as in vivo. Although chemically similar to amprenavir (APV), the potency of TMC114 is substantially greater. To examine the basis for this potency, we solved crystal structures of TMC114 complexed with wt HIV-1 protease and TMC114 and APV complexed with an MDR (L63P, V82T, and I84V) protease variant. In addition, we determined the corresponding binding thermodynamics by isothermal titration calorimetry. TMC114 binds approximately 2 orders of magnitude more tightly to the wt enzyme …
Hydrophobic Sliding: A Possible Mechanism For Drug Resistance In Human Immunodeficiency Virus Type 1 Protease, Jennifer Foulkes-Murzycki, Walter Scott, Celia Schiffer
Hydrophobic Sliding: A Possible Mechanism For Drug Resistance In Human Immunodeficiency Virus Type 1 Protease, Jennifer Foulkes-Murzycki, Walter Scott, Celia Schiffer
Celia A. Schiffer
Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resistance is not understood. From analysis of molecular dynamics simulations, 19 core hydrophobic residues appear to facilitate the conformational changes that occur in HIV-1 protease. The hydrophobic core residues slide by each other, exchanging one hydrophobic van der Waal contact for another, with little energy penalty, while maintaining many structurally important hydrogen bonds. Such hydrophobic sliding may represent a general mechanism by which proteins undergo conformational changes. Mutation of these residues in HIV-1 protease …
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Viability Of A Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights For Better Antiviral Therapy, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
Celia A. Schiffer
Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more …