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CBR Institute for Biomedical Research, Department of Pathology, Harvard Medical School, Boston, MA 02115
We explore the binding sites for mAbs to the 
I domain of the integrin L
2 that can competitively inhibit, allosterically inhibit, or activate binding to the ligand ICAM-1. Ten mAbs, some of them clinically important, were mapped to species-specific residues. The results are interpreted with independent structures of the L I domain determined in seven different crystal lattices and in solution, and which are present in three conformational states that differ in affinity for ligand. Six mAbs bind to adjacent regions of the 1-1 and 3-4 loops, which show only small (mean, 0.8 Å; maximum, 1.8 Å) displacements among the eight I domain structures. Proximity to the ligand binding site and to noncontacting portions of the ICAM-1 molecule explains competitive inhibition by these mAbs. Three mAbs bind to a segment of seven residues in the 5-6 loop and 6 helix, in similar proximity to the ligand binding site, but on the side opposite from the 1-1/3-4 epitopes, and far from noncontacting portions of ICAM-1. These residues show large displacements among the eight structures in response to lattice contacts (mean, 3.6 Å; maximum, 9.4 Å), and movement of a buried Phe in the 5-6 loop is partially correlated with affinity change at the ligand binding site. Together with a lack of proximity to noncontacting portions of ICAM-1, these observations explain variation among this group of mAbs, which can either act as competitive or allosteric antagonists. One agonistic mAb binds distant from the ligand binding site of the I domain, to residues that show little movement (mean, 0.5 Å; maximum, 1.0 Å). Agonism by this mAb is thus likely to result from altering the orientation of the I domain with respect to other domains within an intact integrin L2 heterodimer.
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