2013 Scientific Report

VARI | 2013
Research Interests
Hormone signaling is essential to eukaryotic life. Our research is focused on the signaling mechanisms of physiologically
important hormones, striving to solve fundamental questions that have a broad impact on human health and disease. The
overall goal of my research program is to seek new biological paradigms through structural and functional analysis of key
hormone signaling complexes and to develop therapeutic applications using the structural information we obtain. My current
research programs are focused on two families of proteins, the nuclear hormone receptors and the G protein–coupled
receptors, because these proteins, beyond their fundamental roles in biology, are important drug targets for treating major
human diseases.
Nuclear hormone receptors
Nuclear hormone receptors are a large family comprising ligand-regulated and DNA-binding transcriptional factors, which
include receptors for classic steroid hormones such as estrogen, progesterone, androgens, and glucocorticoids, as well as
receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. One distinguishing fact about
these classic receptors is that they are among the most successful targets in the history of drug discovery. Every receptor has
one or more cognate synthetic ligands being used as medicines. Nuclear receptors also include a class of “orphan” receptors
for which no ligand has been identified. In the last five years, we have developed the following projects centering on the
structural biology of nuclear receptors.
Peroxisome proliferator–activated receptors
The peroxisome proliferator–activated receptors (PPAR a, d, and g) are the key regulators of glucose and fatty acid homeostasis
and as such are important therapeutic targets for treating cardiovascular disease, diabetes, and cancer. Millions of patients
have benefited from treatment with the novel PPARg ligands rosiglitazone and pioglitazone for type II diabetes. To understand
the molecular basis of ligand-mediated signaling by PPARs, we have determined crystal structures of each PPAR’s ligandbinding
domain (LBD) bound to many diverse ligands, including fatty acids, the lipid-lowering drugs called fibrates, and the
new generation of anti-diabetic drugs, the glitazones. We have also determined the crystal structures of these receptors
bound to co-activators or co-repressors, and the crystal structure of PPARg bound to a nitrated fatty acid. These structures
have provided a framework for understanding the mechanisms of agonists and antagonists, as well as the recruitment of
co-activators and co-repressors in gene activation and repression. Furthermore, these structures serve as a molecular basis
for understanding the potency, selectivity, and binding mode of diverse ligands, and have provided crucial insights for designing
the next generation of PPAR medicines. We have discovered a number of natural ligands of PPARg, and our plan is to test
their physiological roles in glucose and insulin regulation, to unravel their molecular and structural mechanisms of action, and
to develop them into therapeutics for diabetes and dislipidemia.
The human glucocorticoid receptor
The human glucocorticoid receptor (GR), the prototype steroid hormone receptor, is crucial for a wide spectrum of human
physiology including immune/inflammatory responses, metabolic homeostasis, and control of blood pressure. GR is a wellestablished
target for drugs, and those drugs have an annual market of over $10 billion. GR ligands such as dexamethasone
(Dex) and fluticasone propionate (FP) are used to treat asthma, leukemia, and autoimmune diseases. However, the clinical use
of these ligands is limited by undesirable side effects partly associated with their receptor cross-reactivity or low potency. The
discovery of potent and more-selective GR ligands—called “dissociated glucocorticoids”, which can separate the good effects
from the bad—remains an intensive goal of pharmaceutical research.
We have determined a number of crystal structures of GR bound to unique ligands and have found an unexpected regulatory
mechanism: GR degradation by lysosomes. We also are studying the molecular and structural mechanisms of the dissociated
glucocorticoids identified by our research.
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