Living cells constantly monitor and respond to their environment by detecting interactions between cell-surface receptors and their ligands. Many such interactions are highly regulated, and in different contexts may or may not occur or may lead to different outcomes. We are interested in the molecular mechanisms by which specific signals are received and transmitted by cell-surface receptors, and how the behavior of these receptors or their ligands is modulated in response to different environments. The principal method we use to study these interactions is X-ray crystallography. By determining the atomic structures of receptors and their ligands we hope to provide a molecular basis for understanding the behavior of these molecules in living systems.

We are currently pursuing studies in two systems. We have recently determined the crystal structures of a ligand-binding fragment of the α 1/β 2 (LFA-1, CD11a/CD18) integrin in conditions permissive and nonpermissive for ligand-binding. These structures have suggested a molecular basis for the variable affinity of this receptor for ligand. We are now pursuing studies of α 1/β 2 ligands and α 1/β 2-ligand complexes to further define the nature of these interactions. In collaboration with the laboratory of Phil Beachy, we have also recently determined the crystal structure of the N-terminal signaling domain of sonic hedgehog (shh-N). This domain is responsible for inducing the formation of new structures in neighboring tissues at several times during embryonic development. The crystal structure of shh-N revealed an unexpected feature that has led to new hypotheses concerning the mechanism of shh-N action. These hypotheses are currently being tested in biochemical and biological systems.

Cho H-S, Leahy DJ. (2002) Structure of the Extracellular Region of HER3 Reveals a Interdomain Tether. Science 278:31479–31485 [PubMed]

C, Limberg BJ, Whitaker GB, Perman B, Leahy DJ. (2002) Characterization of Neuropilin-1 Structural Features That Confer Binding to Semaphorin 3A and Vascular Endothelial Growth Factor 165. J. Biol.Chem. 279:12819-12826 [PubMed]

Dann, C. E., J. C. Hsieh, A. Rattner, D. Sharma, J. Nathans, and D. J. Leahy. (2001) Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 187:1555-1564 [PubMed]

Leahy, D. J., C. E. Dann, 3rd, P. Longo, B. Perman, and K. X. Ramyar. (2000) A mammalian expression vector for expression and purification of secreted proteins for structural studies. Protein Expr. Purif. 188:1633-40 [PubMed]

Beneken, J., J. C. Tu, B. Xiao, M. Nuriya, J. P. Yuan, P. F. Worley, and D. J. Leahy. (2000) Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Neuron 188:2357-68 [PubMed]

Leahy, D. J. (1997) Implications of atomic-resolution structures for cell adhesion. Annu Rev Cell Dev Biol 411:1010-12 [PubMed]

Qu, A., and D. J. Leahy. (1996) The role of the divalent cation in the structure of the I domain from the CD11a/CD18 integrin. Structure 13:529-38 [PubMed]

Qu, A., and D. J. Leahy. (1995) Crystal structure of the I-domain from the CD11a/CD18 (LFA-1, alpha L beta 2) integrin. Proc. Natl. Acad. Sci. USA 21:5184-5194 [PubMed]

Leahy, D. J. (1995) A structural view of CD4 and CD8. FASEB J. 10:693-695 [PubMed]