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Article: Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems

TitleCrystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems
Authors
KeywordsAllosteric modulation
Conformational change
Ferritin
Halogen bond
Stereoisomer
Issue Date2009
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
Faseb Journal, 2009, v. 23 n. 8, p. 2735-2740 How to Cite?
AbstractVolatile anesthetics (VAs), such as isoflurane, induce a general anesthetic state by binding to specific targets (i.e., ion channels) in the central nervous system (CNS). Simultaneously, VAs modulate immune functions, possibly via direct interaction with alternative targets on leukocytes. One such target, the integrin lymphocyte function-associated antigen-1 (LFA-1), has been shown previously to be inhibited by isoflurane. A better understanding of the mechanism by which isoflurane alters protein function requires the detailed information about the drug-protein interaction at an atomic level. Here, we describe the crystal structure of the LFA-1 ligand-binding domain (I domain) in complex with isoflurane at 1.6 Å. We discovered that isoflurane binds to an allosteric cavity previously implicated as critical for the transition of LFA-1 from the low- to the high-affinity state. The isoflurane binding site in the I domain involves an array of amphiphilic interactions, thereby resembling a "common anesthetic binding motif" previously predicted for authentic VA binding sites. These results suggest that the allosteric modulation of protein function by isoflurane, as demonstrated for the integrin LFA-1, might represent a unified mechanism shared by the interactions of volatile anesthetics with targets in the CNS. © FASEB.
Persistent Identifierhttp://hdl.handle.net/10722/125301
ISSN
2015 Impact Factor: 5.299
2015 SCImago Journal Rankings: 2.775
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of Health,AI063421
HL048675
Funding Information:

We thank Koichi Yuki and Sulpicio G. Soriano ( Children's Hospital Boston and Harvard Medical School, Boston, MA, USA) for providing reagents and advice. This work was supported by grants from the National Institutes of Health, AI063421 ( M. S.) and HL048675 ( M. S., J. H. W.).

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorAstrof, NSen_HK
dc.contributor.authorLiu, JHen_HK
dc.contributor.authorWang, JHen_HK
dc.contributor.authorShimaoka, Men_HK
dc.date.accessioned2010-10-31T11:23:17Z-
dc.date.available2010-10-31T11:23:17Z-
dc.date.issued2009en_HK
dc.identifier.citationFaseb Journal, 2009, v. 23 n. 8, p. 2735-2740en_HK
dc.identifier.issn0892-6638en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125301-
dc.description.abstractVolatile anesthetics (VAs), such as isoflurane, induce a general anesthetic state by binding to specific targets (i.e., ion channels) in the central nervous system (CNS). Simultaneously, VAs modulate immune functions, possibly via direct interaction with alternative targets on leukocytes. One such target, the integrin lymphocyte function-associated antigen-1 (LFA-1), has been shown previously to be inhibited by isoflurane. A better understanding of the mechanism by which isoflurane alters protein function requires the detailed information about the drug-protein interaction at an atomic level. Here, we describe the crystal structure of the LFA-1 ligand-binding domain (I domain) in complex with isoflurane at 1.6 Å. We discovered that isoflurane binds to an allosteric cavity previously implicated as critical for the transition of LFA-1 from the low- to the high-affinity state. The isoflurane binding site in the I domain involves an array of amphiphilic interactions, thereby resembling a "common anesthetic binding motif" previously predicted for authentic VA binding sites. These results suggest that the allosteric modulation of protein function by isoflurane, as demonstrated for the integrin LFA-1, might represent a unified mechanism shared by the interactions of volatile anesthetics with targets in the CNS. © FASEB.en_HK
dc.languageengen_HK
dc.publisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/en_HK
dc.relation.ispartofFASEB Journalen_HK
dc.subjectAllosteric modulationen_HK
dc.subjectConformational changeen_HK
dc.subjectFerritinen_HK
dc.subjectHalogen bonden_HK
dc.subjectStereoisomeren_HK
dc.subject.meshAnesthetics, Inhalation - chemistry - pharmacology-
dc.subject.meshApoferritins - chemistry-
dc.subject.meshBinding Sites-
dc.subject.meshIsoflurane - chemistry - pharmacology-
dc.subject.meshLymphocyte Function-Associated Antigen-1 - chemistry - drug effects-
dc.titleCrystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systemsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0892-6638&volume=23&issue=8&spage=2735&epage=2740&date=2009&atitle=Crystal+structure+of+isoflurane+bound+to+integrin+LFA-1+supports+a+unified+mechanism+of+volatile+anesthetic+action+in+the+immune+and+central+nervous+systemsen_HK
dc.identifier.emailZhang, H: hzhang20@hku.hken_HK
dc.identifier.authorityZhang, H=rp00306en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1096/fj.09-129908en_HK
dc.identifier.pmid19332643en_HK
dc.identifier.pmcidPMC2717780-
dc.identifier.scopuseid_2-s2.0-68849109971en_HK
dc.identifier.hkuros174873en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-68849109971&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume23en_HK
dc.identifier.issue8en_HK
dc.identifier.spage2735en_HK
dc.identifier.epage2740en_HK
dc.identifier.eissn1530-6860-
dc.identifier.isiWOS:000268836700041-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridZhang, H=7409196101en_HK
dc.identifier.scopusauthoridAstrof, NS=6508389272en_HK
dc.identifier.scopusauthoridLiu, JH=36066228400en_HK
dc.identifier.scopusauthoridWang, JH=7701330874en_HK
dc.identifier.scopusauthoridShimaoka, M=7004898367en_HK

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