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Article: Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1

TitleStructural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1
Authors
KeywordsCell adhesion
Crystal structure
ICAM-1
Issue Date2009
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 43, p. 18345-18350 How to Cite?
AbstractThe activity of integrin LFA-1 (αLβ2) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of αL chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural features conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules.
Persistent Identifierhttp://hdl.handle.net/10722/125305
ISSN
2014 Impact Factor: 9.674
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthHL48675
CA31798
AI063421
Funding Information:

This work has been supported by National Institutes of Health Grants HL48675 (to J. H. W. and M. S.), CA31798 (to T. A. S.), and AI063421 (to M. S.).

References

 

DC FieldValueLanguage
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorLiu, JHen_HK
dc.contributor.authorYang, Wen_HK
dc.contributor.authorSpringer, Ten_HK
dc.contributor.authorShimaoka, Men_HK
dc.contributor.authorWang, JHen_HK
dc.date.accessioned2010-10-31T11:23:31Z-
dc.date.available2010-10-31T11:23:31Z-
dc.date.issued2009en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 43, p. 18345-18350en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125305-
dc.description.abstractThe activity of integrin LFA-1 (αLβ2) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of αL chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural features conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules.en_HK
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.rightsNational Academy of Sciences. Proceedings. Copyright © National Academy of Sciences.-
dc.subjectCell adhesionen_HK
dc.subjectCrystal structureen_HK
dc.subjectICAM-1en_HK
dc.subject.meshAntibodies - chemistry - immunology-
dc.subject.meshCrystallography, X-Ray-
dc.subject.meshHumans-
dc.subject.meshLymphocyte Function-Associated Antigen-1 - chemistry - immunology-
dc.subject.meshMolecular Mimicry-
dc.titleStructural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=106&issue=43&spage=18345&epage=18350&date=2009&atitle=Structural+basis+of+activation-dependent+binding+of+ligand-mimetic+antibody+AL-57+to+integrin+LFA-1en_HK
dc.identifier.emailZhang, H: hzhang20@hku.hken_HK
dc.identifier.authorityZhang, H=rp00306en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.0909301106en_HK
dc.identifier.pmid19805116en_HK
dc.identifier.pmcidPMC2775275-
dc.identifier.scopuseid_2-s2.0-70849104258en_HK
dc.identifier.hkuros174874en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70849104258&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue43en_HK
dc.identifier.spage18345en_HK
dc.identifier.epage18350en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000271222500055-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridZhang, H=7409196101en_HK
dc.identifier.scopusauthoridLiu, JH=36066228400en_HK
dc.identifier.scopusauthoridYang, W=7407760172en_HK
dc.identifier.scopusauthoridSpringer, T=35450639400en_HK
dc.identifier.scopusauthoridShimaoka, M=7004898367en_HK
dc.identifier.scopusauthoridWang, JH=7701330874en_HK

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