title: Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1.
abstract: The activity of integrin LFA-1 (alpha(L)beta(2)) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of alpha(L) 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.
authors.affiliation: Department of Pediatrics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Zhang
authors.forename: Jin-Huan
authors.initials: JH
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Timothy
authors.initials: T
authors.lastname: Springer
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.forename: Jia-Huai
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000276:immunology; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D018716:Molecular Mimicry; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000906:Antibodies; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D025801:Ubiquitin