Linked Life Data

11371196

Source:http://linkedlifedata.com/resource/pubmed/id/11371196

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
21
pubmed:dateCreated
2001-5-23
pubmed:databankReference
pubmed:abstractText
Herpesvirus proteases belong to a new class of serine proteases and contain a novel Ser-His-His catalytic triad, while classical serine proteases have an acidic residue as the third member. To gain a better understanding of the molecular basis for the functional role of the third-member His residue, we have carried out structural and biochemical investigations of human cytomegalovirus (HCMV) protease that bears mutations of the His157 third member. Kinetic studies showed that all the mutants have reduced catalytic activity. Structural studies revealed that a solvent molecule is hydrogen-bonded to the His63 second member and Ser134 in the H157A mutant, partly rescuing the activity of this mutant. This is confirmed by our kinetic and structural observations on the S134A/H157A double mutant, which showed further reductions in the catalytic activity. The structure of the H157A mutant is also in complex with the PMSF inhibitor. The H157E mutant has the best catalytic activity among the mutants; its structure, however, showed conformational readjustments of the His63 and Ser132 residues. The Ser132-His63 diad of HCMV protease has similar activity as the diads in classical serine proteases, whereas the contribution of the His157 third member to the catalysis is much smaller. Finally, structural comparisons revealed the presence of two conserved structural water molecules at the bottom of the S(1) pocket, suggesting a possible new direction for the design of HCMV protease inhibitors.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
40
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6344-51
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11371196-Alanine, pubmed-meshheading:11371196-Binding Sites, pubmed-meshheading:11371196-Catalytic Domain, pubmed-meshheading:11371196-Conserved Sequence, pubmed-meshheading:11371196-Crystallization, pubmed-meshheading:11371196-Crystallography, X-Ray, pubmed-meshheading:11371196-Cytomegalovirus, pubmed-meshheading:11371196-Dimerization, pubmed-meshheading:11371196-Glutamic Acid, pubmed-meshheading:11371196-Glutamine, pubmed-meshheading:11371196-Histidine, pubmed-meshheading:11371196-Humans, pubmed-meshheading:11371196-Kinetics, pubmed-meshheading:11371196-Mutagenesis, Site-Directed, pubmed-meshheading:11371196-Phenylmethylsulfonyl Fluoride, pubmed-meshheading:11371196-Protease Inhibitors, pubmed-meshheading:11371196-Serine, pubmed-meshheading:11371196-Serine Endopeptidases, pubmed-meshheading:11371196-Solvents
pubmed:year
2001
pubmed:articleTitle
Investigating the role of histidine 157 in the catalytic activity of human cytomegalovirus protease.
pubmed:affiliation
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.