2016 Scientific Report

and antagonists and the recruitment of co-activators and
co-repressors in gene activation and repression. They
also increase our understanding of the potency, selectivity,
and binding mode of ligands and provide crucial insights
for designing the next generation of PPAR medicines. We
have discovered several natural ligands of PPARγ. Our
plan is to test their physiological roles in glucose and insulin
regulation and to develop them into therapeutics
for diabetes and dislipidemia.
The human glucocorticoid receptor
The human glucocorticoid receptor (GR), the prototypical
steroid hormone receptor, affects a wide spectrum
of human physiology including immune/inflammatory
responses, metabolic homeostasis, and control of blood
pressure. GR is a well-established target for drugs, and
those drugs have an annual market of over $10 billion.
However, the clinical use of GR ligands is limited by
undesirable side effects partly resulting from receptor
cross-reactivity or low potency. The discovery of potent,
more-selective GR ligands— “dissociated glucocorticoids”
that have the potential to separate the good effects from the
bad—remains a major goal of pharmaceutical research.
We have determined a number of GR crystal structures
bound to unique ligands and have found an unexpected
regulatory mechanism: degradation by lysosomes. We also
are studying the molecular and structural mechanisms of
the dissociated glucocorticoids identified by our research.
Structural genomics of receptor LBDs
The ligand-binding domain of a nuclear receptor contains
key structural elements that mediate ligand-dependent
regulation of the receptors and, as such, it has been the
focus of intense structural studies. Crystal structures
for most of the 48 human nuclear receptors have been
determined and have illustrated the details of ligand
binding, the conformational changes induced by agonists
and antagonists, the basis of dimerization, and the
mechanism of co-activator and co-repressor binding.
The structures also have provided many surprises about
the identity of ligands and their implications for receptor
signaling pathways. There are only a few “orphan” nuclear
receptors for which the LBD structure remains unsolved.
In the past few years, we have determined the crystal
structures of the LBDs of CAR, SHP, SF-1, COUP-TFII,
and LRH-1, and our structures have helped to identify
new ligands and signaling mechanisms for these orphan
receptors.
G protein–coupled receptors (GPCRs)
The GPCRs form the largest family of receptors in the
human genome and account for over 40% of drug targets,
but their structures remain a challenge because they
are seven-transmembrane receptors. There are only
a few crystal structures for class A GPCRs, and many
important questions regarding GPCR ligand binding and
activation remain unanswered. From our standpoint,
GPCRs are similar to nuclear hormone receptors with
respect to regulation by protein-ligand and protein–protein
interactions. We focus on class B GPCRs, which includes
receptors for parathyroid hormone (PTH), corticotropinreleasing
factor (CRF), glucagon, and glucagon-like
peptide-1. We have determined crystal structures of the
ligand-binding domain of the PTH receptor and the CRF
receptor, and we are developing hormone analogs for
treating osteoporosis, depression, and diabetes. We are
developing a mammalian overexpression system and plan
to use it to express full-length GPCRs for crystallization and
structural studies.
RECENT PUBLICATIONS
He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015.
Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035.
Kang, Yanyong, X. Edward Zhou, Xiang Gao, Yuanzheng He, Wei Liu, Andrii Ishchenko, Anton Barty, Thomas A. White, Oleksandr
Yefanov, et al. 2015. Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523(7562): 561–567.
28 Van Andel Research Institute | Scientific Report