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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Crystal Structures Of Human Ctbp In Complex With Substrate Mtob Reveal Active Site Features Useful For Inhibitor Design, Brendan Hilbert, Steven Grossman, Celia Schiffer, William Royer
Crystal Structures Of Human Ctbp In Complex With Substrate Mtob Reveal Active Site Features Useful For Inhibitor Design, Brendan Hilbert, Steven Grossman, Celia Schiffer, William Royer
Celia A. Schiffer
The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD(+) phosphate. Neither feature is present in other d2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors. Elsevier B.V. All …
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Celia A. Schiffer
HIV-1 protease is a major drug target for AIDS therapy. With the appearance of drug-resistant HIV-1 protease variants, understanding the mechanism of drug resistance becomes critical for rational drug design. Computational methods can provide more details about inhibitor-protease binding than crystallography and isothermal titration calorimetry. The latest FDA-approved HIV-1 protease inhibitor is Darunavir (DRV). Herein, each DRV atom is evaluated by free energy component analysis for its contribution to the binding affinity with wild-type protease and ACT, a drug-resistant variant. This information can contribute to the rational design of new HIV-1 protease inhibitors.
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate …
Evaluating The Substrate-Envelope Hypothesis: Structural Analysis Of Novel Hiv-1 Protease Inhibitors Designed To Be Robust Against Drug Resistance, Madhavi Nalam, Akbar Ali, Michael Altman, G. S. Kiran Kumar Reddy, Sripriya Chellappan, Visvaldas Kairys, Aysegul Ozen, Hong Cao, Michael Gilson, Bruce Tidor, Tariq Rana, Celia Schiffer
Evaluating The Substrate-Envelope Hypothesis: Structural Analysis Of Novel Hiv-1 Protease Inhibitors Designed To Be Robust Against Drug Resistance, Madhavi Nalam, Akbar Ali, Michael Altman, G. S. Kiran Kumar Reddy, Sripriya Chellappan, Visvaldas Kairys, Aysegul Ozen, Hong Cao, Michael Gilson, Bruce Tidor, Tariq Rana, Celia Schiffer
Celia A. Schiffer
Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type …