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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>
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