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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structural Basis of G Protein-coupled Receptor-G<sub>i</sub> Protein Interaction</title><author><name sortKey="Mnpotra, Jagjeet S" sort="Mnpotra, Jagjeet S" uniqKey="Mnpotra J" first="Jagjeet S." last="Mnpotra">Jagjeet S. Mnpotra</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Qiao, Zhuanhong" sort="Qiao, Zhuanhong" uniqKey="Qiao Z" first="Zhuanhong" last="Qiao">Zhuanhong Qiao</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Cai, Jian" sort="Cai, Jian" uniqKey="Cai J" first="Jian" last="Cai">Jian Cai</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Lynch, Diane L" sort="Lynch, Diane L" uniqKey="Lynch D" first="Diane L." last="Lynch">Diane L. Lynch</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Grossfield, Alan" sort="Grossfield, Alan" uniqKey="Grossfield A" first="Alan" last="Grossfield">Alan Grossfield</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Leioatts, Nicholas" sort="Leioatts, Nicholas" uniqKey="Leioatts N" first="Nicholas" last="Leioatts">Nicholas Leioatts</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Hurst, Dow P" sort="Hurst, Dow P" uniqKey="Hurst D" first="Dow P." last="Hurst">Dow P. Hurst</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Pitman, Michael C" sort="Pitman, Michael C" uniqKey="Pitman M" first="Michael C." last="Pitman">Michael C. Pitman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Song, Zhao Hui" sort="Song, Zhao Hui" uniqKey="Song Z" first="Zhao-Hui" last="Song">Zhao-Hui Song</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Reggio, Patricia H" sort="Reggio, Patricia H" uniqKey="Reggio P" first="Patricia H." last="Reggio">Patricia H. Reggio</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24855641</idno><idno type="pmc">4106340</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106340</idno><idno type="RBID">PMC:4106340</idno><idno type="doi">10.1074/jbc.M113.539916</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000368</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structural Basis of G Protein-coupled Receptor-G<sub>i</sub> Protein Interaction</title><author><name sortKey="Mnpotra, Jagjeet S" sort="Mnpotra, Jagjeet S" uniqKey="Mnpotra J" first="Jagjeet S." last="Mnpotra">Jagjeet S. Mnpotra</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Qiao, Zhuanhong" sort="Qiao, Zhuanhong" uniqKey="Qiao Z" first="Zhuanhong" last="Qiao">Zhuanhong Qiao</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Cai, Jian" sort="Cai, Jian" uniqKey="Cai J" first="Jian" last="Cai">Jian Cai</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Lynch, Diane L" sort="Lynch, Diane L" uniqKey="Lynch D" first="Diane L." last="Lynch">Diane L. Lynch</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Grossfield, Alan" sort="Grossfield, Alan" uniqKey="Grossfield A" first="Alan" last="Grossfield">Alan Grossfield</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Leioatts, Nicholas" sort="Leioatts, Nicholas" uniqKey="Leioatts N" first="Nicholas" last="Leioatts">Nicholas Leioatts</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Hurst, Dow P" sort="Hurst, Dow P" uniqKey="Hurst D" first="Dow P." last="Hurst">Dow P. Hurst</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Pitman, Michael C" sort="Pitman, Michael C" uniqKey="Pitman M" first="Michael C." last="Pitman">Michael C. Pitman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Song, Zhao Hui" sort="Song, Zhao Hui" uniqKey="Song Z" first="Zhao-Hui" last="Song">Zhao-Hui Song</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Reggio, Patricia H" sort="Reggio, Patricia H" uniqKey="Reggio P" first="Patricia H." last="Reggio">Patricia H. Reggio</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Background:</bold> CB<sub>2</sub> couples with only G<sub>i</sub> protein.</p><p><bold>Results:</bold> Cross-linking studies using LC-MS/MS and ESI-MS/MS identified three specific CB<sub>2</sub>-Gα<sub>i</sub> cross-link sites. MD showed an orientation change from the β2-AR*/G<sub>s</sub> geometry makes all cross-links possible.</p><p><bold>Conclusion:</bold> Second intracellular loop of CB<sub>2</sub> interactions are key for G<sub>i</sub> complex formation.</p><p><bold>Significance:</bold> Findings should be relevant for other GPCRs that couple to G<sub>i</sub> proteins.</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">J Biol Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name><publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24855641</article-id><article-id pub-id-type="pmc">4106340</article-id><article-id pub-id-type="publisher-id">M113.539916</article-id><article-id pub-id-type="doi">10.1074/jbc.M113.539916</article-id><article-categories><subj-group subj-group-type="heading"><subject>Signal Transduction</subject></subj-group></article-categories><title-group><article-title>Structural Basis of G Protein-coupled Receptor-G<sub>i</sub> Protein Interaction</article-title><subtitle>FORMATION OF THE CANNABINOID CB<sub>2</sub> RECEPTOR-G<sub>i</sub> PROTEIN COMPLEX<xref ref-type="fn" rid="FN1">*</xref></subtitle><alt-title alt-title-type="short">Formation of Activated CB<sub>2</sub> Receptor Gα<sub>i1</sub>β<sub>1</sub>γ<sub>2</sub> Protein Complex</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Mnpotra</surname><given-names>Jagjeet S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Qiao</surname><given-names>Zhuanhong</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cai</surname><given-names>Jian</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lynch</surname><given-names>Diane L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Grossfield</surname><given-names>Alan</given-names></name><xref ref-type="aff" rid="aff3"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leioatts</surname><given-names>Nicholas</given-names></name><xref ref-type="aff" rid="aff3"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hurst</surname><given-names>Dow P.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pitman</surname><given-names>Michael C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff4"><sup>‖</sup></xref></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>Zhao-Hui</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reggio</surname><given-names>Patricia H.</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="corresp" rid="cor2"><sup>2</sup></xref></contrib><aff id="aff1">From the<label>‡</label>Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina 27402,</aff><aff id="aff2">the<label>§</label>Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292,</aff><aff id="aff3">the<label>¶</label>Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York 14642, and</aff><aff id="aff4">the<label>‖</label>Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598</aff></contrib-group><author-notes><corresp id="cor1"><label>1</label> To whom correspondence may be addressed. E-mail: <email>zhsong@louisville.edu</email>.</corresp><corresp id="cor2"><label>2</label> To whom correspondence may be addressed: <addr-line>Dept. of Chemistry and Biochemistry, University of North Carolina, Patricia A. Sullivan Science Bldg., P. O. Box 26170, Greensboro, NC 27402-6170.</addr-line> Tel.: <phone>336-334-5333</phone>; Fax: <fax>336-334-5402</fax>; E-mail: <email>phreggio@uncg.edu</email>.</corresp></author-notes><pub-date pub-type="ppub"><day>18</day><month>7</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>22</day><month>5</month><year>2014</year></pub-date><volume>289</volume><issue>29</issue><fpage>20259</fpage><lpage>20272</lpage><history><date date-type="received"><day>9</day><month>12</month><year>2013</year></date><date date-type="rev-recd"><day>18</day><month>5</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.</copyright-statement><copyright-year>2014</copyright-year></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc02914020259.pdf"></self-uri><abstract abstract-type="teaser"><p><bold>Background:</bold> CB<sub>2</sub> couples with only G<sub>i</sub> protein.</p><p><bold>Results:</bold> Cross-linking studies using LC-MS/MS and ESI-MS/MS identified three specific CB<sub>2</sub>-Gα<sub>i</sub> cross-link sites. MD showed an orientation change from the β2-AR*/G<sub>s</sub> geometry makes all cross-links possible.</p><p><bold>Conclusion:</bold> Second intracellular loop of CB<sub>2</sub> interactions are key for G<sub>i</sub> complex formation.</p><p><bold>Significance:</bold> Findings should be relevant for other GPCRs that couple to G<sub>i</sub> proteins.</p></abstract><abstract><p>In this study, we applied a comprehensive G protein-coupled receptor-Gα<sub>i</sub> protein chemical cross-linking strategy to map the cannabinoid receptor subtype 2 (CB<sub>2</sub>)- Gα<sub>i</sub> interface and then used molecular dynamics simulations to explore the dynamics of complex formation. Three cross-link sites were identified using LC-MS/MS and electrospray ionization-MS/MS as follows: 1) a sulfhydryl cross-link between C3.53(134) in TMH3 and the Gα<sub>i</sub> C-terminal i-3 residue Cys-351; 2) a lysine cross-link between K6.35(245) in TMH6 and the Gα<sub>i</sub> C-terminal i-5 residue, Lys-349; and 3) a lysine cross-link between K5.64(215) in TMH5 and the Gα<sub>i</sub> α<sub>4</sub>β<sub>6</sub> loop residue, Lys-317. To investigate the dynamics and nature of the conformational changes involved in CB<sub>2</sub>·G<sub>i</sub> complex formation, we carried out microsecond-time scale molecular dynamics simulations of the CB<sub>2</sub> R*·Gα<sub>i1</sub>β<sub>1</sub>γ<sub>2</sub> complex embedded in a 1-palmitoyl-2-oleoyl-phosphatidylcholine bilayer, using cross-linking information as validation. Our results show that although molecular dynamics simulations started with the G protein orientation in the β2-AR*·Gα<sub>s</sub>β<sub>1</sub>γ<sub>2</sub> complex crystal structure, the Gα<sub>i1</sub>β<sub>1</sub>γ<sub>2</sub> protein reoriented itself within 300 ns. Two major changes occurred as follows. 1) The Gα<sub>i1</sub> α5 helix tilt changed due to the outward movement of TMH5 in CB<sub>2</sub> R*. 2) A 25° clockwise rotation of Gα<sub>i1</sub>β<sub>1</sub>γ<sub>2</sub> underneath CB<sub>2</sub> R* occurred, with rotation ceasing when Pro-139 (IC-2 loop) anchors in a hydrophobic pocket on Gα<sub>i1</sub> (Val-34, Leu-194, Phe-196, Phe-336, Thr-340, Ile-343, and Ile-344). In this complex, all three experimentally identified cross-links can occur. These findings should be relevant for other class A G protein-coupled receptors that couple to G<sub>i</sub> proteins.</p></abstract><kwd-group><kwd>Cannabinoid Receptor</kwd><kwd>G Protein-coupled Receptor (GPCR)</kwd><kwd>Mass Spectrometry (MS)</kwd><kwd>Molecular Dynamics</kwd><kwd>Signal Transduction</kwd></kwd-group><funding-group><award-group><funding-source id="CS100">National Institutes of Health</funding-source><award-id rid="CS100">DA011551</award-id><award-id rid="CS100">GM095496</award-id><award-id rid="CS100">DA003934</award-id><award-id rid="CS100">DA021358</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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