Molecular basis of resistance to HIV-1 protease inhibition: a plausible hypothesis

Biochemistry
I LuqueE Freire

Abstract

The binding thermodynamics of the HIV-1 protease inhibitor acetyl pepstatin and the substrate Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln, corresponding to one of the cleavage sites in the gag, gag-pol polyproteins, have been measured by direct microcalorimetric analysis. The results indicate that the binding of the peptide substrate or peptide inhibitor is entropically driven; i.e., it is characterized by an unfavorable enthalpy and a favorable entropy change, in agreement with a structure-based thermodynamic analysis based upon an empirical parameterization of the energetics. Dissection of the binding enthalpy indicates that the intrinsic interactions are favorable and that the unfavorable enthalpy originates from the energy cost of rearranging the flap region in the protease molecule. In addition, the binding is coupled to a negative heat capacity change. The dominant binding force is the increase in solvent entropy that accompanies the burial of a significant hydrophobic surface. Comparison of the binding energetics obtained for the substrate with that obtained for synthetic nonpeptide inhibitors indicates that the major difference is in the magnitude of the conformational entropy change. In solution, the peptide substrate has a hi...Continue Reading

References

Jan 1, 1993·Annual Review of Biochemistry·A Wlodawer, J W Erickson

❮ Previous
Next ❯

Citations

Dec 3, 2008·Amino Acids·Ling-Ling WuHong-Wen Gao
Sep 3, 2013·Analytical Biochemistry·Arne SchönErnesto Freire
Sep 7, 1999·Bioorganic & Medicinal Chemistry Letters·M D Shultz, J Chmielewski
Nov 23, 2006·Physical Chemistry Chemical Physics : PCCP·Jens Carlsson, Johan Aqvist
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·E Freire
Dec 14, 2004·Journal of Biomolecular Structure & Dynamics·Melik C Demirel, Ozlem Keskin
Oct 25, 2000·Protein Science : a Publication of the Protein Society·A Velazquez-CampoyE Freire
May 16, 2009·BMC Structural Biology·Ling-Ling WuLing Chen
Oct 14, 2011·Viruses·Akbar AliCelia A Schiffer
Jun 11, 2009·The Journal of Chemical Physics·Dechang LiYonggang Huang
Jun 9, 2001·Archives of Biochemistry and Biophysics·A Velazquez-CampoyE Freire
May 17, 2001·Proceedings of the National Academy of Sciences of the United States of America·A Velazquez-CampoyE Freire
Feb 6, 2007·Drug Discovery Today·Viktor Hornak, Carlos Simmerling
Jun 26, 2003·Protein Science : a Publication of the Protein Society·Etsuko KatohRieko Ishima
May 3, 2012·Protein Science : a Publication of the Protein Society·Oscar AlvizoCelia A Schiffer
Jul 28, 2010·Chemical Biology & Drug Design·Alexander L PerrymanC David Stout
Dec 6, 2005·Journal of Molecular Graphics & Modelling·Adina-Luminiţa MilacAndrei-José Petrescu
Sep 8, 2010·Biophysical Journal·Nevra OzerTurkan Haliloglu
Dec 2, 2004·Progress in Biophysics and Molecular Biology·Hiroyasu Ohtaka, Ernesto Freire
Oct 14, 1998·Journal of Molecular Biology·M J ToddE Freire
Mar 20, 2001·Journal of Molecular Biology·I Jelesarov, M Lu
Aug 29, 2016·Analytical Biochemistry·Arne Schön, Ernesto Freire
Aug 2, 2003·The Journal of Biological Chemistry·Aurel PopescuConstantin T Craescu
Mar 30, 2001·The Journal of Biological Chemistry·R D BrokxG I Makhatadze
Mar 17, 1999·Nature·T N Schumacher
Oct 1, 2008·Journal of Enzyme Inhibition and Medicinal Chemistry·Sandra KrauchencoIgor Polikarpov
Jun 26, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·D J GordonS C Meredith
Dec 15, 2020·Protein Science : a Publication of the Protein Society·Shahid N KhanRieko Ishima

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Allergy & Infectious Diseases (ASM)

Allergies result from the hyperreactivity of the immune system to some environmental substance and can be life-threatening. Infectious diseases are caused by organisms including bacteria, viruses, fungi and parasites. They can be transmitted different ways, such as person-to-person. Here is the latest research on allergy and infectious diseases.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Allergy & Infectious Diseases

Allergies result from the hyperreactivity of the immune system to some environmental substance and can be life-threatening. Infectious diseases are caused by organisms including bacteria, viruses, fungi and parasites. They can be transmitted different ways, such as person-to-person. Here is the latest research on allergy and infectious diseases.