Function-related conformational dynamics of G protein–coupled receptors revealed by NMR
G protein–coupled receptors (GPCRs) function as receptors for various neurotransmitters, hormones, cytokines, and metabolites. GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a chara...
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| Veröffentlicht in: | Biophysical reviews 2019-06, Vol.11 (3), p.409-418 |
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| creator | Ueda, Takumi Kofuku, Yutaka Okude, Junya Imai, Shunsuke Shiraishi, Yutaro Shimada, Ichio |
| description | G protein–coupled receptors (GPCRs) function as receptors for various neurotransmitters, hormones, cytokines, and metabolites. GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a characteristic level of ability to activate or deactivate its target, which is referred to as its efficacy. The ligand efficacies and biased signaling of GPCRs remarkably affect the therapeutic properties of the ligands. However, these features of GPCRs can only be partially understood from the crystallography data, although numerous GPCR structures have been solved. NMR analyses have revealed that GPCRs have multiple interconverting substates, exchanging on various timescales, and that the exchange rates are related to the ligand efficacies and biased signaling. In addition, NMR analyses of GPCRs in the lipid bilayer environment of rHDLs revealed that the exchange rates are modulated by the lipid bilayer environment, highlighting the importance of the function-related dynamics in the lipid bilayer. In this review, we will describe several solution NMR studies that have clarified the conformational dynamics related to the ligand efficacy and biased signaling of GPCRs. |
| doi_str_mv | 10.1007/s12551-019-00539-w |
| format | Article |
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GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a characteristic level of ability to activate or deactivate its target, which is referred to as its efficacy. The ligand efficacies and biased signaling of GPCRs remarkably affect the therapeutic properties of the ligands. However, these features of GPCRs can only be partially understood from the crystallography data, although numerous GPCR structures have been solved. NMR analyses have revealed that GPCRs have multiple interconverting substates, exchanging on various timescales, and that the exchange rates are related to the ligand efficacies and biased signaling. In addition, NMR analyses of GPCRs in the lipid bilayer environment of rHDLs revealed that the exchange rates are modulated by the lipid bilayer environment, highlighting the importance of the function-related dynamics in the lipid bilayer. In this review, we will describe several solution NMR studies that have clarified the conformational dynamics related to the ligand efficacy and biased signaling of GPCRs.</description><identifier>ISSN: 1867-2450</identifier><identifier>EISSN: 1867-2469</identifier><identifier>DOI: 10.1007/s12551-019-00539-w</identifier><identifier>PMID: 31102199</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Arrestin ; Biochemistry ; Biological and Medical Physics ; Biological Techniques ; Biomedical and Life Sciences ; Biophysics ; Cell Biology ; Crystallography ; Cytokines ; Deactivation ; Effectiveness ; Foreign exchange rates ; G protein-coupled receptors ; Hormones ; Life Sciences ; Ligands ; Lipid bilayers ; Lipids ; Membrane Biology ; Metabolites ; Nanotechnology ; Neurotransmitters ; NMR ; Nuclear magnetic resonance ; Proteins ; Receptor mechanisms ; Receptors ; Review ; Signaling</subject><ispartof>Biophysical reviews, 2019-06, Vol.11 (3), p.409-418</ispartof><rights>International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019</rights><rights>Copyright Springer Nature B.V. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c492w-15777d7165d082dadc4f8e654134ac15c45b8b1ac900764345fa0065347374eb3</citedby><cites>FETCH-LOGICAL-c492w-15777d7165d082dadc4f8e654134ac15c45b8b1ac900764345fa0065347374eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557943/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557943/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31102199$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ueda, Takumi</creatorcontrib><creatorcontrib>Kofuku, Yutaka</creatorcontrib><creatorcontrib>Okude, Junya</creatorcontrib><creatorcontrib>Imai, Shunsuke</creatorcontrib><creatorcontrib>Shiraishi, Yutaro</creatorcontrib><creatorcontrib>Shimada, Ichio</creatorcontrib><title>Function-related conformational dynamics of G protein–coupled receptors revealed by NMR</title><title>Biophysical reviews</title><addtitle>Biophys Rev</addtitle><addtitle>Biophys Rev</addtitle><description>G protein–coupled receptors (GPCRs) function as receptors for various neurotransmitters, hormones, cytokines, and metabolites. GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a characteristic level of ability to activate or deactivate its target, which is referred to as its efficacy. The ligand efficacies and biased signaling of GPCRs remarkably affect the therapeutic properties of the ligands. However, these features of GPCRs can only be partially understood from the crystallography data, although numerous GPCR structures have been solved. NMR analyses have revealed that GPCRs have multiple interconverting substates, exchanging on various timescales, and that the exchange rates are related to the ligand efficacies and biased signaling. In addition, NMR analyses of GPCRs in the lipid bilayer environment of rHDLs revealed that the exchange rates are modulated by the lipid bilayer environment, highlighting the importance of the function-related dynamics in the lipid bilayer. In this review, we will describe several solution NMR studies that have clarified the conformational dynamics related to the ligand efficacy and biased signaling of GPCRs.</description><subject>Arrestin</subject><subject>Biochemistry</subject><subject>Biological and Medical Physics</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biophysics</subject><subject>Cell Biology</subject><subject>Crystallography</subject><subject>Cytokines</subject><subject>Deactivation</subject><subject>Effectiveness</subject><subject>Foreign exchange rates</subject><subject>G protein-coupled receptors</subject><subject>Hormones</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Lipid bilayers</subject><subject>Lipids</subject><subject>Membrane Biology</subject><subject>Metabolites</subject><subject>Nanotechnology</subject><subject>Neurotransmitters</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Proteins</subject><subject>Receptor mechanisms</subject><subject>Receptors</subject><subject>Review</subject><subject>Signaling</subject><issn>1867-2450</issn><issn>1867-2469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kbtO5DAUhi20iPsLUKBI29AEfHfcIK0QN4mLhKCgshzHgaDEztoJo-l4B96QJ8HDwABbbOWjc77z279_ALYR3EMQiv2IMGMoh0jmEDIi88kSWEMFFzmmXP5a1AyugvUYHyHkFBdsBawShCBGUq6Bu-PRmaHxLg-21YOtMuNd7UOnZ03dZtXU6a4xMfN1dpL1wQ-2ca_PL8aPfZvwYI3tBx9iqp6snrXKaXZ5cb0JlmvdRrv1cW6A2-Ojm8PT_Pzq5Ozwz3luqMSTHDEhRCUQZxUscKUrQ-vCckYRodogZigrixJpI5NlTglltU5GGKGCCGpLsgEO5rr9WHa2MtYNQbeqD02nw1R53aifE9c8qHv_pDhjQlKSBHY_BIL_O9o4qK6JxratdtaPUWFMMGSUC57Q3_-gj34M6ZveqQJiVsgiUXhOmeBjDLZePAZBNUtOzZNTKTn1npyapKWd7zYWK59RJYDMgZhG7t6Gr7v_I_sGzOal9g</recordid><startdate>20190601</startdate><enddate>20190601</enddate><creator>Ueda, Takumi</creator><creator>Kofuku, Yutaka</creator><creator>Okude, Junya</creator><creator>Imai, Shunsuke</creator><creator>Shiraishi, Yutaro</creator><creator>Shimada, Ichio</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190601</creationdate><title>Function-related conformational dynamics of G protein–coupled receptors revealed by NMR</title><author>Ueda, Takumi ; Kofuku, Yutaka ; Okude, Junya ; Imai, Shunsuke ; Shiraishi, Yutaro ; Shimada, Ichio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c492w-15777d7165d082dadc4f8e654134ac15c45b8b1ac900764345fa0065347374eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Arrestin</topic><topic>Biochemistry</topic><topic>Biological and Medical Physics</topic><topic>Biological Techniques</topic><topic>Biomedical and Life Sciences</topic><topic>Biophysics</topic><topic>Cell Biology</topic><topic>Crystallography</topic><topic>Cytokines</topic><topic>Deactivation</topic><topic>Effectiveness</topic><topic>Foreign exchange rates</topic><topic>G protein-coupled receptors</topic><topic>Hormones</topic><topic>Life Sciences</topic><topic>Ligands</topic><topic>Lipid bilayers</topic><topic>Lipids</topic><topic>Membrane Biology</topic><topic>Metabolites</topic><topic>Nanotechnology</topic><topic>Neurotransmitters</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Proteins</topic><topic>Receptor mechanisms</topic><topic>Receptors</topic><topic>Review</topic><topic>Signaling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ueda, Takumi</creatorcontrib><creatorcontrib>Kofuku, Yutaka</creatorcontrib><creatorcontrib>Okude, Junya</creatorcontrib><creatorcontrib>Imai, Shunsuke</creatorcontrib><creatorcontrib>Shiraishi, Yutaro</creatorcontrib><creatorcontrib>Shimada, Ichio</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ueda, Takumi</au><au>Kofuku, Yutaka</au><au>Okude, Junya</au><au>Imai, Shunsuke</au><au>Shiraishi, Yutaro</au><au>Shimada, Ichio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Function-related conformational dynamics of G protein–coupled receptors revealed by NMR</atitle><jtitle>Biophysical reviews</jtitle><stitle>Biophys Rev</stitle><addtitle>Biophys Rev</addtitle><date>2019-06-01</date><risdate>2019</risdate><volume>11</volume><issue>3</issue><spage>409</spage><epage>418</epage><pages>409-418</pages><issn>1867-2450</issn><eissn>1867-2469</eissn><abstract>G protein–coupled receptors (GPCRs) function as receptors for various neurotransmitters, hormones, cytokines, and metabolites. GPCR ligands impart differing degrees of signaling in the G protein and arrestin pathways, in phenomena called biased signaling, and each ligand for a given GPCR has a characteristic level of ability to activate or deactivate its target, which is referred to as its efficacy. The ligand efficacies and biased signaling of GPCRs remarkably affect the therapeutic properties of the ligands. However, these features of GPCRs can only be partially understood from the crystallography data, although numerous GPCR structures have been solved. NMR analyses have revealed that GPCRs have multiple interconverting substates, exchanging on various timescales, and that the exchange rates are related to the ligand efficacies and biased signaling. In addition, NMR analyses of GPCRs in the lipid bilayer environment of rHDLs revealed that the exchange rates are modulated by the lipid bilayer environment, highlighting the importance of the function-related dynamics in the lipid bilayer. In this review, we will describe several solution NMR studies that have clarified the conformational dynamics related to the ligand efficacy and biased signaling of GPCRs.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>31102199</pmid><doi>10.1007/s12551-019-00539-w</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Arrestin Biochemistry Biological and Medical Physics Biological Techniques Biomedical and Life Sciences Biophysics Cell Biology Crystallography Cytokines Deactivation Effectiveness Foreign exchange rates G protein-coupled receptors Hormones Life Sciences Ligands Lipid bilayers Lipids Membrane Biology Metabolites Nanotechnology Neurotransmitters NMR Nuclear magnetic resonance Proteins Receptor mechanisms Receptors Review Signaling |
| title | Function-related conformational dynamics of G protein–coupled receptors revealed by NMR |
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