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Nitric Oxide-Mediated Inhibition Of Hdm2-P53 Binding, Christopher Schonhoff, Marie-Claire Daou, Stephen Jones, Celia Schiffer, Alonzo Ross
Nitric Oxide-Mediated Inhibition Of Hdm2-P53 Binding, Christopher Schonhoff, Marie-Claire Daou, Stephen Jones, Celia Schiffer, Alonzo Ross
Celia A. Schiffer
It has become increasingly evident that nitric oxide exerts its effects, in part, by S-nitrosylation of cysteine residues. We tested in vitro whether nitric oxide may indirectly control p53 by S-nitrosylation and inactivation of the p53 negative regulator, Hdm2. Treatment of Hdm2 with a nitric oxide donor inhibits Hdm2-p53 binding, a critical step in Hdm2 regulation of p53. The presence of excess amounts of cysteine or dithiothreitol blocks this inhibition of binding. Moreover, nitric oxide inhibition of Hdm2-p53 binding was found to be reversible. Sulfhydryl sensitivity and reversibility are consistent with nitrosylation. Finally, we have identified a critical cysteine residue …
Crystal Structure Of Lysine Sulfonamide Inhibitor Reveals The Displacement Of The Conserved Flap Water Molecule In Human Immunodeficiency Virus Type 1 Protease, Madhavi Nalam, Anik Peeters, Tim Jonckers, Inge Dierynck, Celia Schiffer
Crystal Structure Of Lysine Sulfonamide Inhibitor Reveals The Displacement Of The Conserved Flap Water Molecule In Human Immunodeficiency Virus Type 1 Protease, Madhavi Nalam, Anik Peeters, Tim Jonckers, Inge Dierynck, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site …
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 …
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Celia A. Schiffer
The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements …