title: Effects of remote mutation on the autolysis of HIV-1 PR: X-ray and NMR investigations.
abstract: Autolysis rates of the C95M and C95M/C1095A mutants of a HIV-1 protease tethered dimer have been determined by real time NMR and it is observed that the double mutant has approximately two times higher rate. X-ray structure of the C95M/C1095A double mutant has been solved and refined to 2.1 A resolution. Comparison of the double mutant structure with that of C95M single mutant reveals that there is a shift in the position of the catalytic aspartates and the bound catalytic water. The mutation also causes a loss of hydrophobic packing near the dimerization domain of the protein. These observations demonstrate that subtle changes are adequate to cause significant changes in the rate of autolysis of the double mutant. This provides a rationale for the effects of remote mutations on the activity and drug resistance of the enzyme.
authors.affiliation: Solid State Physics Division, Bhabha Atomic Research Centre, Mumbai 400 005, India.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: K K
authors.initials: KK
authors.lastname: Kannan
authors.forename: M V
authors.initials: MV
authors.lastname: Hosur
authors.forename: Neel S
authors.initials: NS
authors.lastname: Bhavesh
authors.forename: Amarnath
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Rohit
authors.initials: R
authors.lastname: Mittal
authors.forename: R V
authors.initials: RV
authors.lastname: Hosur
mesh_terms: D019943:Amino Acid Substitution; D002384:Catalysis; D020134:Catalytic Domain / Q000502:physiology; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D016333:HIV Protease