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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The mechanism of rate-limiting motions in enzyme function</title><author><name sortKey="Watt, Eric D" sort="Watt, Eric D" uniqKey="Watt E" first="Eric D." last="Watt">Eric D. Watt</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Shimada, Hiroko" sort="Shimada, Hiroko" uniqKey="Shimada H" first="Hiroko" last="Shimada">Hiroko Shimada</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Kovrigin, Evgenii L" sort="Kovrigin, Evgenii L" uniqKey="Kovrigin E" first="Evgenii L." last="Kovrigin">Evgenii L. Kovrigin</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Loria, J Patrick" sort="Loria, J Patrick" uniqKey="Loria J" first="J. Patrick" last="Loria">J. Patrick Loria</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">17615241</idno><idno type="pmc">1924554</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1924554</idno><idno type="RBID">PMC:1924554</idno><idno type="doi">10.1073/pnas.0702551104</idno><date when="2007">2007</date><idno type="wicri:Area/Pmc/Corpus">000062</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000062</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The mechanism of rate-limiting motions in enzyme function</title><author><name sortKey="Watt, Eric D" sort="Watt, Eric D" uniqKey="Watt E" first="Eric D." last="Watt">Eric D. Watt</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Shimada, Hiroko" sort="Shimada, Hiroko" uniqKey="Shimada H" first="Hiroko" last="Shimada">Hiroko Shimada</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Kovrigin, Evgenii L" sort="Kovrigin, Evgenii L" uniqKey="Kovrigin E" first="Evgenii L." last="Kovrigin">Evgenii L. Kovrigin</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Loria, J Patrick" sort="Loria, J Patrick" uniqKey="Loria J" first="J. Patrick" last="Loria">J. Patrick Loria</name><affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The ability to use conformational flexibility is a hallmark of enzyme function. Here we show that protein motions and catalytic activity in a RNase are coupled and display identical solvent isotope effects. Solution NMR relaxation experiments identify a cluster of residues, some distant from the active site, that are integral to this motion. These studies implicate a single residue, histidine-48, as the key modulator in coupling protein motion with enzyme function. Mutation of H48 to alanine results in loss of protein motion in the isotope-sensitive region of the enzyme. In addition, <italic>k</italic><sub>cat</sub> decreases for this mutant and the kinetic solvent isotope effect on <italic>k</italic><sub>cat</sub>, which was 2.0 in WT, is near unity in H48A. Despite being located 18 Å from the enzyme active site, H48 is essential in coordinating the motions involved in the rate-limiting enzymatic step. These studies have identified, of ≈160 potential exchangeable protons, a single site that is integral in the rate-limiting step in RNase A enzyme function.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">17615241</article-id><article-id pub-id-type="pmc">1924554</article-id><article-id pub-id-type="publisher-id">6928</article-id><article-id pub-id-type="doi">10.1073/pnas.0702551104</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biophysics</subject></subj-group></subj-group></article-categories><title-group><article-title>The mechanism of rate-limiting motions in enzyme function</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Watt</surname><given-names>Eric D.</given-names></name><xref rid="aff1" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Shimada</surname><given-names>Hiroko</given-names></name><xref rid="aff1" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Kovrigin</surname><given-names>Evgenii L.</given-names></name><xref rid="aff1" ref-type="aff"></xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Loria</surname><given-names>J. Patrick</given-names></name><xref rid="aff1" ref-type="aff"></xref><xref ref-type="corresp" rid="cor1"><sup>†</sup></xref></contrib><aff id="aff1">Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520</aff></contrib-group><author-notes><corresp id="cor1"><sup>†</sup>To whom correspondence should be addressed. E-mail: <email>patrick.loria@yale.edu</email></corresp><fn fn-type="edited-by"><p>Edited by Gordon G. Hammes, Duke University Medical Center, Durham, NC, and approved May 30, 2007</p></fn><fn fn-type="con"><p>Author contributions: E.D.W. and J.P.L. designed research; E.D.W., H.S., and E.L.K. performed research; E.D.W., H.S., and J.P.L. analyzed data; and J.P.L. wrote the paper.</p></fn><fn id="FN1" fn-type="present-address"><p>*Present address: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226.</p></fn></author-notes><pub-date pub-type="ppub"><day>17</day><month>7</month><year>2007</year></pub-date><pub-date pub-type="epub"><day>5</day><month>7</month><year>2007</year></pub-date><volume>104</volume><issue>29</issue><fpage>11981</fpage><lpage>11986</lpage><history><date date-type="received"><day>19</day><month>3</month><year>2007</year></date></history><copyright-statement>© 2007 by The National Academy of Sciences of the USA</copyright-statement><copyright-year>2007</copyright-year><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zpq02907011981.pdf"></self-uri><abstract><p>The ability to use conformational flexibility is a hallmark of enzyme function. Here we show that protein motions and catalytic activity in a RNase are coupled and display identical solvent isotope effects. Solution NMR relaxation experiments identify a cluster of residues, some distant from the active site, that are integral to this motion. These studies implicate a single residue, histidine-48, as the key modulator in coupling protein motion with enzyme function. Mutation of H48 to alanine results in loss of protein motion in the isotope-sensitive region of the enzyme. In addition, <italic>k</italic><sub>cat</sub> decreases for this mutant and the kinetic solvent isotope effect on <italic>k</italic><sub>cat</sub>, which was 2.0 in WT, is near unity in H48A. Despite being located 18 Å from the enzyme active site, H48 is essential in coordinating the motions involved in the rate-limiting enzymatic step. These studies have identified, of ≈160 potential exchangeable protons, a single site that is integral in the rate-limiting step in RNase A enzyme function.</p></abstract><kwd-group><kwd>Carr–Purcell–Meiboom–Gill dispersion</kwd><kwd>enzyme dynamics</kwd><kwd>NMR</kwd><kwd>protein motions</kwd><kwd>RNase A</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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