Cindy Benod

is working on identifying ligands that affect coregulator binding to LRH-1 to modulate the nuclear receptor responses in breast cancer cell lines. The identified ligands would be starting compounds for a new generation of pharmaceuticals for treatment of breast cancer. She is studying the interaction between the orphan nuclear receptors Dax-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1; NROB1) and liver receptor homolog 1 (LRH-1, NR5A2). Dax-1 is a potent corepressor of nuclear receptors and inhibits transactivation of the liver receptor homolog 1 (LRH-1) through direct interaction. Her primary goal is to develop a strategy using Biacore experiments to identify ligands able to block the interaction between these two nuclear receptors.

A secondary focus is the interactions between Dax-1 and other nuclear receptors like androgen receptor (AR, NR3C4), Nur77 (NGFI-B) and estrogen related receptors (ERRs, NR3B).

Leslie Cruz

Leslie’s project is to probe the behavior mediated by androgen receptor in brain. She will do this in collaboration with Professor Nirao Shah, who will construct transgenic mice that express an engineered androgen receptor, which only responds to a unique testosterone derivative that Leslie will design, synthesize and test. Leslie has already obtained one unique testosterone for testing and is designing a variant androgen receptor that will only respond to this testosterone analog.

She has also designed a second series of testosterone analogs (at the C17 position) and will synthesize and test these, if the current compound fails in animal trials. The ultimate goal of this research is to make compounds that are tissue specific so that we can learn the roles of the receptor in muscle, bone, prostate and brain. Therapeutics that spare other tissues, while effectively blocking androgen receptor in prostate, may be designed from Leslie’s research results.

Eva Estébanez-Perpiñá

The androgen receptor (AR) belongs to the nuclear receptor family, and is a key regulator of prostate cancer growth. AR is therefore a crucial target for prostate cancer therapies. We have obtained structural information of the AR hormone binding domain (LBD) in complex with peptides derived from the AR physiological coactivators ARA70 and P160 family of coactivators (i.e. GRIP1 and RAC3). These structural models of the protein-peptide complexes determined by X-ray crystallography clarify the long standing question of why the same surface on the AR LBD is unique amongst the nuclear receptors in its capability to bind to different classes of domains, characterized by hydrophobic sequence motifs, presented by its coactivator partners. We hope to inhibit AR activation by blocking this surface AR LBD-coregulatory proteins interaction, proposing a structure-based drug design combining our structural information, combinatorial chemistry (in collaboration with several Organic Chemistry labs at UCSF), and bioinformatics. Eva's primary goal will be the development of a new therapeutic approach to treat prostate cancer using the molecular insights gained from these complexes.

Peter Hwang

is studying the androgen receptor (AR) and its associations with coactivator proteins. His project is to define critical interactions between the SRC family of coactivators with the N terminal domain of the androgen receptor and to develop the structural basis for first drug candidates that block androgen receptor function by disrupting these interactions. Peter is also working on the crystallographic structures of clathrin subunits, in collaboration with Frances Brodsky and Joel Ybe, to determine the structural basis of regulated clathrin assembly in the processes of endocytosis and membrane trafficking.

Natalia Jouravel

The androgen receptor (AR) is the clinically and biochemically identified regulator of prostate cancer growth. Blocking AR transcriptional activity is the major non-surgical treatment for prostate cancer. Clinical success of antiandrogens (e. g. cyproterone acetate, flutamide) is limited by weak binding affinity, low selectivity or emerging agonist activity which usually occurs in advanced prostate cancers. Better pharma-ceutical treatments for prostate cancer require that we understand the mechanism of AR repression. The goal is to uncover structural principles and mechanisms of AR inhibition. AR action can be blocked by endogenous repressors or by synthetic chemical agents. Natalia's focus is the interplay of the biological and chemical repression, working on determination of the structure of AR in complex with its repressor, Small Heterodimer Partner (SHP), to learn how AR transcription is naturally regulated in target tissues. She plans to obtain a crystal structure of AR in complex with a novel antiandrogen compound, a derivative of 11b-nortestosterone.

Sam Pfaff

researches the structural and biochemical properties of glucocorticoid receptor (GR) activation. Structures of the GR LBD will be solved in complex with various hormones and co-activator peptides to elucidate the mechanism of co-activator selection. He is also helping to determine an antagonist bound androgen receptor structure.

Elena Sablin

works on projects in several different areas. In the nuclear receptor field, she is studying the X-ray crystal structures of the steroidogenic factor 1 (SF-1) and its relative, liver receptor homologue 1 (LRH-1), in collaboration with Holly Ingraham in the Department of Physiology at UCSF. She is also conducting structural studies on SF-1 and LRH-1 complexes with cofactors and cofactor peptides. Elena is also working on the structure of the myosin tail domain in collaboration with Jim Spudich at Stanford. Finally, Elena is studying nucleotide-dependent conformational changes in actin and F-actin fragment structures in collaboration with John Dawson at the University of Guelph.

Eric Slivka's

focus is the ligand binding domain (LBD) of v-erbA, a mutant form of the thyroid hormone receptor (TR). He is performing mutational studies to determine which of the v-erbA LBD's nine point mutations have the greatest effect on v-erbA's lack of ligand binding ability in comparison to wild-type chicken TR. He is also determining the x-ray crystal structure of the v-erbA LBD alone and in complex with various nuclear receptor corepressor peptides. In addition, he is working on x-ray crystal structure projects involving several other TR constructs and complexes.

Fumiaki Yumoto

studies engineered proteases targeting cancer cells in collaboration with Catalyst Biosciences, Inc. This research aims to find proteases with novel substrate specificities that can attack disease-related molecules (such as those involved in several types of human cancers) and analyze their three dimensional structures with inhibitors that will provide insight into their substrate specificities. Fumiaki's contribution in this project, using crystallography and multidimensional NMR, will lead to a better understanding of these molecules interactions and molecular mechanisms for specificity. The engineered proteases may eventually become an important new class of therapeutics for human cancers.

Maia Vinogradova

works on the regulation of the kinesin motor. Her two projects on kinesin regulation are : 1) crystallization of the kinesin-like calmodulin binding protein (KCBP) in the complex with its regulator, either calmodulin or a novel single EF-hand, plant specific protein KIC, and 2)  crystallization of the complex of the kinesin CENP-E and its cargo binding protein – protein kinase BUBR1 which is involved in mitotic checkpoint.

Maia is also studying the skeletal muscle ternary complex in both relaxed and calcium-activated forms. The goal of this project is to find a drug capable of increasing the muscle strength and Ca2+-sensitivity of muscle contractions.

Maia previously determined the structure of troponin with and without calcium.

Jeremy Wilbur's

focus is structural characterization of endocytic proteins, primarily clathrin and HIP1 (huntingtin interacting protein -1). Clathrin is the prototypical coat protein that assembles into a polyhedral lattice on the cytosolic side of the plasma membrane. In response to a signaling event, clathrin alters its assembled conformation to form a coated vesicle, thereby internalizing and down regulating cell surface receptors. Current projects are looking at the mechanism of clathrin assembly and its regulation by phosphorylation and HIP1. Structures for a few fragments of clathrin have been solved but structure based mechanisms of regulation are still lacking. Jeremy is primarily using crystallography to understand how HIP1 interacts with clathrin and how this interaction may be inhibited. This may play a significant role in developing new cancer therapeutics. In addition to crystallography, biochemical and cell biological assays are also employed to understand the role of phosphorylation in regulating clathrin assembly. These assays include immunofluoresence and flow cytometry, surface plasmon resonance and standard biochemistry.