Professor
Department of Biophysics and Biophysical Chemistry
School of Medicine

dleahy@jhmi.edu

703 Hunterian Building
725 N. Wolfe Street
Baltimore, MD 21205

Office: 410-614-2534
Lab: 410-614-2533

We are interested in molecular mechanisms governing activity of signaling pathways in both normal and disease states. To address this problem, we express pathway components for biochemical, biophysical and X-ray crystallographic studies.  Our current studies focus on two general areas: the Hedgehog pathway and signaling mediated by specific receptor tyrosine kinases, in particular members of the EGF receptor (ErbB) family. 

Hedgehog proteins play critical roles in tissue differentiation during animal development.  Elaborate molecular mechanisms have thus evolved to regulate Hedgehog signaling in time and place, and defects in Hedgehog signaling underlie human disorders ranging from birth defects to cancer. Our studies have elucidated the nature and strength of interactions between Hedgehog proteins and key pathway components, identified essential co-factors for specific interactions, and provided a molecular framework for understanding how these interactions contribute to the complex regulation of Hedgehog activity observed in living systems.  We are currently extending our studies to additional pathway components.

The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases also mediates key signaling events during animal development, and abnormal signaling figures prominently in many human diseases, notably cancer.  Our work has demonstrated an autoinhibited form for ErbB receptors in the absence of ligand with the sole exception of HER2, which has no known ligand. We have shown that HER2 adopts a constitutively active-like structure that explains many of its unique properties and has influenced the development of drugs targeting HER2 in human cancers.  We are currently investigating correlations between different ErbB conformations and signaling activity through structural and biophysical studies of additional ErbBs, related receptors, and designed receptor variants.

Selected Publications
Qiu, C., M.K. Tarrant, T. Boronina, P.A. Longo, J.M. Kavran, R.M. Cole, P.A. Cole, and D.J. Leahy. (2009) In vitro enzymatic characterization of near full length EGFR in activated and inhibited states. Biochemistry 48:6624-6632.

McLellan, J.S., X. Zheng, G. Hauk, R. Ghirlando, P.A. Beachy, and D.J. Leahy. (2008) The mode of Hedgehog binding to Ihog homologs is not conserved across different phyla. Nature 455:979-983.

Leahy, D.J. (2008) A molecular view of anti-ErbB monoclonal antibody therapy. Cancer Cell 13:291-293.

Qiu, C., M.K. Tarrant, S.H. Choi, A. Sathyamurthy, R. Bose, S. Banjade, A. Pal, W.G. Bornmann, M.A. Lemmon, P.A. Cole, and D.J. Leahy. (2008) Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 16:460-467.

Suh, Y., G. Atzmon, M.-O. Cho, D. Hwang, B. Liu, D.J. Leahy, N. Barzilai, and P. Cohen. (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. USA 105:3438-3442.

Qiu, C., S. Lienhard, N.E. Hynes, A. Badache, and D.J. Leahy. (2008) Memo Is homologous to nonheme iron dioxygenases and binds an ErbB2-derived phosphopeptide in its vestigial active site. J. Biol. Chem. (2008) 283:2734-2740.

Huang, G.N., D.L. Huso, S. Bouyain, J. Tu, K.A. McCorkell, M.J. May, Y. Zhu, M. Lutz, S. Collins, M. Dehoff, S. Kang, K. Whartenby, J. Powell, D.J. Leahy, and P.F. Worley. (2008) NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319:476-481.

Vander Kooi, C.W., M.A. Jusino, B. Perman, D.B. Neau, H.D. Bellamy, and D.J. Leahy. (2007) Structural basis for ligand and heparin binding to Neuropilin B domains. Proc. Natl. Acad. Sci. USA 104:6152-6157.

Zhang, F., J.S. McLellan, A. Ayala-Jiménez, D.J. Leahy, and R.J. Linhardt. (2007) Kinetic and structural studies on interactions between heparin/heparan sulfate and proteins of the Hedgehog signaling pathway. Biochemistry 46:3933-3941.

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

Bouyain, S., P.A. Longo, S. Li, K.M. Ferguson, and D.J. Leahy. (2005) The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc. Natl. Acad. Sci. USA 102:15024-15029.

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