Date Published:Oct 27
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.
Zhang, HongminLiu, Jin-HuanYang, WeiSpringer, TimothyShimaoka, MotomuWang, Jia-HuaiAI063421/AI/NIAID NIH HHS/United StatesCA31798/CA/NCI NIH HHS/United StatesHL48675/HL/NHLBI NIH HHS/United StatesResearch Support, N.I.H., ExtramuralUnited StatesProceedings of the National Academy of Sciences of the United States of AmericaProc Natl Acad Sci U S A. 2009 Oct 27;106(43):18345-50. Epub 2009 Sep 23.