Research Interests:

Living cells constantly monitor and respond to their environment by detecting
interactions between cell-surface receptors and their ligands. We are interested
in the molecular mechanisms by which specific signals are received and transmitted
by cell-surface receptors. Active components of receptors and ligands are
expressed and their properties studied by both biochemical and X-ray
crystallographic methods. These studies are designed to provide a molecular
basis for understanding the behavior of specific molecules in living systems.

We are currently pursuing studies in three related systems. In collaboration with
the laboratories of Phil Beachy and Jeremy Nathans here at Hopkins, we are
investigating the molecular mechanisms employed by specific signaling pathways
during animal development. In particular, we have determined the crystal structures
of components of both the Hedgehog and Wnt signaling pathways as well as
complementary biochemical and mutagenesis studies. We are pursuing studies of additional molecules involved in each of these pathways and hope to develop an understanding of the molecular events that take place at each step in the signaling cascade. Developmental signaling pathways are of particular interest because
signaling during animal development must be restricted in time and place, and the molecular features of these pathways often reveal unique solutions to this
problem. Defects in these signaling pathways are frequently found in human
diseases including many forms of cancer, and understanding these pathways
may have important implications for human health.

We are also pursuing studies of members of the epidermal growth factor receptor
(EGFR) families as well as molecules involved in axon guidance. Each of these
systems presents interesting questions concerning the nature of interactions
between receptors and ligands, how these interactions are regulated, and how
these interactions are integrated to build and maintain a living organism. Study of
these systems invariably establishes unexpected links to other signaling pathways
thatprovide insight into the function and evolution of these molecules.

PDB Structures: deposited coordinates

Publications:

Vander Kooi, C.W., Jusino, M.A., Perman, B., Neau, D.B., Bellamy, H.D., and Leahy, D.J. (2007) “Structural basis for ligand andheparin binding to Neuropilin B domains” Proc. Natl. Acad. Sci. USA, Apr 10;104(15):6152-7.
PubMed

McLellan, J.S., Yao, S., Zheng, X., Geisbrecht, B.V., Ghirlando, R, Beachy, P.A., and Leahy, D.J. (2006) "Structure of a heparin-dependent complex of Hedgehog and Ihog" Proc. Natl. Acad. Sci USA, Nov. 14;103(46):17208-13.
PubMed

Bouyain, S., Longo, P.A., Li, S., Ferguson, K.M., and Leahy, D.J. (2005) “The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand.” Proc Natl Acad Sci U S A. Oct 18;102(42):15024-9.
PubMed

Franklin, MC, Carey, K.D., Vajdos, F.F., Leahy, D.J., de Vos, A.M.,and Sliwkowski, M.X. “Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex” Cancer Cell, (2004);5(4): 317-328.
PubMed

Cho,H.S.,Mason,K.,Ramyar,K.X.,Stanley,A.M.,Gabelli,S.B.,Denney,Jr.,D.W.,Leahy,D.J. (2003) ”Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab”, Nature 421:756-760.
PubMed