Active Projects
Inhibitors for Androgen Receptor Activation Surfaces
This project focuses on discovery of the compounds that bind the AR surface and inhibit the assembly of AR-coreactivator complexes necessary for gene transcription by using fast three-dimensional screening methods. We are using high throughput crystallography to perform fast track chemistry leading to a new class of androgen receptor (AR) antagonists. Blocking protein associations necessary for function represents an alternative approach to inhibiting AR action. We seek small organic molecules that bind to hot spots on the human AR coactivator-binding interface. Multiple, weak binding fragments will be identified and visualized bound to AR using high throughput X-ray crystallography. Using these three-dimensional surface maps, standard chemistry will be used to link the fragments creating high affinity molecules that block the receptor's protein associations and aberrant AR mediated gene transcription.
Dept. of Defense Prostate Cancer Research Program
(Collaborators: John Baxter, Paul Webb, Kevin Shokat)
Understanding Substrate Specificity through Therapeutically Targeted, Specific Serine Proteases
The Fletterick laboratory is working with Catalyst Biosciences, Inc. to determine the three dimensional structures of proteases specificity-programmed to attack critical cell surface molecules. Structural data on Catalyst`s engineered proteases complexed with target-like peptides will provide a framework to understand direct and second shell side chain interactions in substrate specificity. The overall objective is understanding targeting determinants in proteases designed to disable proteins critical for maintaining cancer.
UC Discovery Program in Biotechnology
Novel Inhibitors of Nuclear Receptor Function
Objectives are development of novel "drug-like" inhibitors that specifically prevent the interaction of nuclear receptors with their coregulating proteins through their NR box binding site, and functionally block transcriptional activation by nuclear receptors. The research design integrates knowledge based structure, chemistry, and cell biology to rationally produce novel small molecule inhibitors of the targeted protein interaction. Methods are high throughput screening, parallel chemistry, medicinal chemistry, high throughput X-ray crystallography (structural genomics), cell biology, genomics, and pharmacology.
NIH RO1 (R.K. Guy, St. Judes)
Folding of Androgen Receptor-Coregulator Complex
This project will study stable complexes of N-terminal androgen receptor domain fragments with partnering domains of a representative subset of coregulator proteins, and screen the paired combinations to discover synergistic folding domains for stable complexes. These studies will reveal interactions necessary to design pharmaceuticals directed to the N-terminal receptor domain in controlling prostate cancer.
NIH R21 (R.J. Fletterick)
Structure and Function of Molecular Motors
Project V: Structural Studies on Motor Proteins. This project moves the focus of the X-ray crystallography component of this program project from analysis of the motility mechanisms of molecular motors towards an atomic level analysis of their regulation and attachments to protein partners. We plan to define the role of the neck domain in the kinesin homolog KinI which drives the remarkable catastrophic breakdown of tubulin, to learn how Ca ion regulates kinesin binding to microtubules, and to reveal how the tubulin dimer affects KinI function. We will crystallize the catalytic domain of myosin with a fragment of an actin polymer, to compare myosin-track interactions with kinesin-track interactions. Finally we will characterize the binding domain that connects vesicles to the myosin motor of myosin V, a vesicle transporter in neurons. NIH Program Project (Roger Cooke, PI)
