Department of Chemistry

Home > People > Faculty

UNC-CH Collaborators

Steve Matson

Vytas Bankaitis

Nancy Thompson

Elizabeth Wilson

Matthew Wolfgang

Muhammad Yousaf

	Redinbo Group Recent Results

	Human Nuclear Receptor LRH-1 and Breast Cancer Development

	We have elucidated the structural basis of ligand binding by the former orphan receptor liver receptor homologue-1 (LRH-1). Using a combination of crystallographic and mass spectrometry studies, we showed that phospholipids bind in the large, hydrophobic pocket of this receptor. We further demonstrated that mutations eliminating phospholipid binding effectively destroy receptor activity in transcriptional assays. Thus, we have adopted this receptor as a ligand-regulated factor and are currently examining its role in generating local estrogen hormone to feed breast cancer development. CLICK IMAGE TO ENLARGE Ortlund, E.A., Lee, Y., Solomon, I.H., Hager, J.M., Safi, R., Choi, Y., Guan, Z., Tripathy, A., Raetz, C.R.H., McDonnell, D.P., Moore, D.D., and Redinbo, M.R. (2005). Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nature Structural and Molecular Biology, 12, 357-363.


	Transcriptional Control by a Monomeric Nuclear Receptor

	We recently reported the crystal structure of the DNA binding domain (DBD) of the monomeric nuclear receptor LRH-1 in complex with duplex DNA. This DBD is unique in the nuclear receptor family because it contains a so-called Ftz-F1 extension, which we find terminates in a helix that packs against the Zn-binding portion of the protein (shown in yellow below). Using structural and functional data, we find that the position of this Ftz-F1 helix is critical for receptor activity by properly orienting the remainder of the protein to recruit transcriptional cofactors.



	Solomon, I.H., Hager, J.M., Safi, R., McDonnell, D.P., Redinbo, M.R., and Ortlund, E.A. (2005). Crystal Structure of the Human LRH-1 DBD DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity. Journal of Molecular Biology, in press.




	Drug Processing by the Promiscuous Human Enzyme hCE1

	Human carboxylesterase 1 (hCE1) is a broad-spectrum drug metabolism enzyme found in abundance in liver, the central organ for xenobiotic detoxification. We have recently shown how hCE1 uses two binding clefts, one at the active site and one at a surface site, to impact there bioavailability of the anticancer drug tamoxifen, the cholesterol-lowering compound mevastatin CLICK IMAGE TO ENLARGE Fleming, C.D., Bencharit, S., Edwards, C.C., Hyatt, J.L., Tsurkan, L., Feng, B., Fraga, C., Morton, C.L., Howard-Williams, E.L., Potter, P.M., and Redinbo, M.R. (2005). Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin and inhibition by benzil. Journal of Molecular Biology, in press.

Department of Chemistry
Campus Box 3290
Caudill and Kenan Laboratories
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 USA
Phone: (919) 843-7100