Raj Kumar, PhD
Raj Kumar, PhD, is director of research and a professor of biochemistry in the Department of Basic Sciences. He received his PhD and did his postdoctoral work at the University of Texas Medical Branch at Galveston. His research focuses on biochemistry, cell biology, molecular biology, protein biochemistry, structural biology and biophysical chemistry, thermodynamics of protein folding/unfolding, cancer biology, pharmacology and pathology of gastrointestinal tract, diabetes, signal transduction, post transcriptional modifications, endocrinology, biology of nuclear hormone receptors, inflammation, allergy and asthma.
Steroid 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 online.
Student research opportunities
Understanding the relationships between steroid hormone receptor (SHR) function and structure is the current focus of Dr. 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.
List of selected publications (from a total of more than 100 publications)
- 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. Full Text
- 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, 1987-1999, 2014. Full Text
- Simons SS, Edwards DP, and Kumar R. Dynamic Structures of Nuclear Hormone Receptors: New Promises and Challenges. Molecular Endocrinology, 28, 173-82, 2014. Full Text
- 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. Full Text
- 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. Full Text
- Kumar R, and McEwan IJ. Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation. Endocrine Reviews, 33, 271-299, 2012. Full Text
- 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. Full Text
- Ahmad N, and Kumar R. Steroid hormone receptors in cancer development: A target for cancer therapeutics. Cancer Letters, 300, 1-9, 2011. Full Text
- 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. Full Text
- 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). Full Text
- 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. Full Text
- 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. Full Text
- 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. Full Text
- 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. Full Text
- 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. Full Text
- Kumar R, and Pasricha PJ. Thiazolium compounds for treating gastrointestinal complications. US Patent No: WO/2009/023207, 2009.
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, Texas