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Article: Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1
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TitleStructural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1
 
AuthorsZhang, H2 1
Liu, JH2
Yang, W2 4 3
Springer, T2 4
Shimaoka, M2 4
Wang, JH2
 
KeywordsCell adhesion
Crystal structure
ICAM-1
 
Issue Date2009
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 43, p. 18345-18350 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0909301106
 
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.
 
ISSN0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
DOIhttp://dx.doi.org/10.1073/pnas.0909301106
 
PubMed Central IDPMC2775275
 
ISI Accession Number IDWOS:000271222500055
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.).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorZhang, H
 
dc.contributor.authorLiu, JH
 
dc.contributor.authorYang, W
 
dc.contributor.authorSpringer, T
 
dc.contributor.authorShimaoka, M
 
dc.contributor.authorWang, JH
 
dc.date.accessioned2010-10-31T11:23:31Z
 
dc.date.available2010-10-31T11:23:31Z
 
dc.date.issued2009
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 43, p. 18345-18350 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0909301106
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.0909301106
 
dc.identifier.eissn1091-6490
 
dc.identifier.epage18350
 
dc.identifier.hkuros174874
 
dc.identifier.isiWOS:000271222500055
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.).

 
dc.identifier.issn0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
dc.identifier.issue43
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2775275
 
dc.identifier.pmid19805116
 
dc.identifier.scopuseid_2-s2.0-70849104258
 
dc.identifier.spage18345
 
dc.identifier.urihttp://hdl.handle.net/10722/125305
 
dc.identifier.volume106
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.rightsNational Academy of Sciences. Proceedings. Copyright © National Academy of Sciences.
 
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.subjectCell adhesion
 
dc.subjectCrystal structure
 
dc.subjectICAM-1
 
dc.titleStructural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Harvard Medical School
  3. Beijing Novo Nordisk Pharmaceuticals Sci and Tech Co. Ltd.
  4. Children's Hospital Boston