Raj Kumar, PhD
Professor of Biochemistry
Bachelor - University of Lucknow, Lucknow, India
Master - University of Lucknow, Lucknow, India
PhD - University of Lucknow, Lucknow, India
Postdoctoral - University of Texas Medical Branch, Galveston, TX
Structure: function studies of the steroid hormone receptors
hormone receptors (SHRs) act in a cell-type and promoter specific
manner. SHRs have modular structure consisting of three major functional
domains, ligand binding- (LBD), DNA binding- (DBD), and N-terminal-
(NTD) domains. Ligand-bound receptor interacts with its specific DNA
response element and/or other transcription factors to regulate genes.
The basic workings of the DBD and LBD of the SHRs are known through a
combination of molecular and structural biological approaches. However,
little is known about AF1, located in the NTD of SHRs. AF1 structure has
been difficult to determine because in solutions AF1 seems to exist as a
random ensemble of conformers. In terms of sequence homology AF1 domain
is the least conserved among the SHRs compared to other parts. It is
known to interact with other transcription factors, and conditional
folding has been reported to be the key for these interactions and
subsequent gene regulation. How and what kind of conformation AF1 adopts
is an open question. Our laboratory is focused on solving some of these
structural/functional issues pertaining to the AF1 of the SHRs. We and
others have first time discovered methods that might be folding AF1 into
functional conformations. In collaboration with structural biologists at
our center as well as out of the campus, we use state-of-art biophysical
techniques such as circular dichroism (CD)-, infrared (FTIR)-, NMR and
mass- spectroscopies, and X-ray crystallography.
Our research is supported by a grant from National
Institute of Diabetes and Digestive and Kidney Disorders. Read more
details of the grant
List of Selected Publications (From a total of more than 100
Goswami D, Pascal B, Kumar R, Edwards DP, and
Griffin PR. Structural dynamics and inter domain crosstalk of
PR-TBP interaction probed by hydrogen/deuterium exchange Mass
Spectrometry. Structure-Cell, 22, 961-973, 2014.
Singh CK, George J, Nihal M, Sabat G, Kumar R,
and Ahmad N. Novel Downstream Molecular Targets of SIRT1 in
Melanoma: A Quantitative Proteomics Approach. Oncotarget, 5,
Simons SS, Edwards DP, and Kumar R. Dynamic
Structures of Nuclear Hormone Receptors: New Promises and
Challenges. Molecular Endocrinology, 28, 173-82, 2014.
Kumar R, Moure CM, Khan SH, Callaway C, Grimm
S, Goswami D, Griffin PR, and Edwards DP. Regulation of the
structurally dynamic disordered amino-terminal domain of
progesterone receptor by protein induced folding. Journal of
Biological Chemistry, 288, 30285-30299, 2013.
Khan SH, Awasthi S, Guo C, Goswami D, Ling J, Griffin PR,
Simons, SS, and Kumar R. Binding of the amino
terminal region of coactivator TIF2 to the intrinsically
disordered AF1 domain of the glucocorticoid receptor is
accompanied by conformational reorganizations. Journal of
Biological Chemistry, 287, 44546-44560, 2012.
Kumar R, and McEwan IJ. Allosteric modulators
of steroid hormone receptors: structural dynamics and gene
regulation. Endocrine Reviews, 33, 271-299, 2012.
Savidge T, Urvil P, Oezguen N, Braun W, Pinchuk I, Torres A,
English R, Wiktorowitz J, Kumar R, Stamler J,
and Pothoulakis C. Host S-nitrosylation inhibits clostridial
small molecule-activated autoprocessing toxins. Nature
Medicine, 17, 1136-1141, 2011.
Ahmad N, and Kumar R. Steroid hormone receptors
in cancer development: A target for cancer therapeutics. Cancer
Letters, 300, 1-9, 2011.
Atamna H, and Kumar R. Potential therapies to
prevent mitochondrial dysfunction and malformation of toxic Aβ
peptides in Alzheimer’s Disease. Journal of Alzheimer’s
Disease, 20, S439-452, 2010.
Garza AS, Khan SH, and Kumar R. Site-specific
phosphorylation induces functionally active conformation in the
intrinsically disordered N-terminal activation function domain
(AF1) of the glucocorticoid receptor. Molecular and Cellular
Biology, 30, 220-230, 2010. (Selected for Research Highlight).
Salama SA, Kamel MW, Diaz-Arrastia CR, Xu X, Veenstra TD, Salih
S, Botting SK, and Kumar R. Effect of TNF-ά on
estrogen metabolism and homeostasis in endometrial cells: A
potential relevance to physiological and pathological processes
in endometrium. Journal of Clinical Endocrinology and
Metabolism, 94, 285-93, 2009.
Kumar R, Volk DE, Li J, Gorenstein DG, Lee JC,
and Thompson EB. TBP binding induces structure in the
recombinant glucocorticoid receptor AF1 domain. Proceedings
of the National Academy of Sciences USA, 101, 16425-16430, 2004.
Kumar R, Lee JC, Bolen DW, and Thompson EB. The
conformation of the glucocorticoid receptor AF1/tau1 domain
induced by osmolyte binds co-regulatory Proteins. Journal of
Biological Chemistry, 276, 18146-18152, 2001.
Kumar R, Baskakov IV, Srinivasan G, Bolen DW,
Lee JC, and Thompson EB. Inter-domain signaling in a two-domain
fragment of the human glucocorticoid receptor. Journal of
Biological Chemistry, 274, 24737-24741, 1999.
Baskakov IV, Kumar R, Srinivasan G, Ji Y, Bolen
DW, and Thompson EB. Trimethylamine N-oxide-induced cooperative
folding of an intrinsically unfolded transcription-activating
fragment of human glucocorticoid receptor. Journal of
Biological Chemistry, 274, 10693-10696, 1999.
Kumar R, and Pasricha PJ. Thiazolium compounds
for treating gastrointestinal complications. US Patent No:
Research Opportunities in Dr. Kumar’s Lab:
Understanding the relationships between steroid hormone receptor (SHR)
function and structure is the current focus of Dr. Raj Kumar’s research.
Intrinsically disordered (ID) sequences within proteins are unstructured
regions that are associated with cell signaling and human diseases.
Steroid hormone receptors (SHRs) are ligand-dependent intracellular
transcription factors and are essential regulators of key physiological
processes as well as important therapeutic targets in several diseases
including inflammation, hormone-dependent cancers, osteoporosis, and
cardiovascular disease. Despite the fact that full receptor activity
requires a concerted effect of both AF1 and AF2 activation domains, and
that AF1 is critical for cell and target gene specificity of SHRs, the
current design of selective receptor modulators (SRMs) for clinical uses
is primarily based on their effects on AF2, thereby missing the whole
SHR signaling spectrum. A better understanding of how AF1 mediates
cell/tissue and target gene specific responses is essential for improved
therapeutic targeting of SHRs. Our lab is investigating to identify
targets that act outside of the AF2 pocket, which could complement or
replace AF2-based existing SRMs.