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, H1 2
Liu, JH1
Yang, W1 3 4
Springer, T1 4
Shimaoka, M1 4
Wang, JH1
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
2011 Impact Factor: 9.681
2011 SCImago Journal Rankings: 1.754
DOIhttp://dx.doi.org/10.1073/pnas.0909301106
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.).

PubMed Central IDPMC2775275
ReferencesReferences in Scopus
DC Field
Value
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.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
2011 Impact Factor: 9.681
2011 SCImago Journal Rankings: 1.754
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
Author Affiliations
  1. Harvard Medical School
  2. The University of Hong Kong
  3. Beijing Novo Nordisk Pharmaceuticals Sci and Tech Co. Ltd.
  4. Children's Hospital Boston