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Scripps Research Joint Appointments

Director, Translational Research Institute
Faculty, Kellogg School of Science and Technology

Research Focus

Group Members: M. J. Chalmers, N. Kumar, R. D. Garcia-Ordonez, D. Marciano, G. West, D. Goswami, J. Lauer, D. Kuruvilla, S. Novick, B. Pascal, M. Chang, A. Corzo (former members of the lab: S.A. Busby, R. Landgraf, S. Willis, M. Istrate, D. Policastro, C. Griffin, E. Tracy, J. Zhang, X. Zhang, S. Dai, S. Prasad).

Structural and Chemical Biology of Enzymes and Receptors Involved in Cancer, Metabolic Disease, and Autoimmune Disorders
Our group combines chemical, cellular, and structural biology to study mechanism and structure-function of enzymes and receptors; particularly kinases (i.e, AMP Kinase), G-protein coupled receptors (GPCRs) and nuclear receptors (NRs). During the past few years we have focused on developing hydrogen/deuterium exchange (HDX) technology for probing the mechanism of activation of intact nuclear receptor complexes. Specifically we have used HDX, chemical libraries and cell-based assays to better understand ligand activation and co-receptor/co-factor interaction within the vitamin D receptor (VDR) and the peroxisome proliferator-activated receptor gamma (PPARG) complex. We have applied HDX and chemical approaches to the study of the orphan nuclear receptors LRH-1 and RORA/RORB/RORG. These receptors have been implicated in cancer, metabolic and immune disorders.

Mechanistic studies of ligand activation of Nuclear Receptors
HDX was applied to the characterization of ligand activation of the vitamin D receptor (VDR) in complex with its co-receptor retinoid X receptor (RXR) and probed the dynamics of the functional domains of both VDR and RXR as a function of ligand and DNA interaction. As shown in our 2011 paper in NSMB, these data demonstrate the role of DNA interaction in the functional state of the VDR/RXR heterodimer complex by directly controlling conformational mobility of surfaces of the receptor complex that interact with NR co-factors. Currently HDX is being used to guide lead optimization and SAR of selective VDR modulators (VDRMs).

Probing ligand interaction with GPCRs
GPCRs are an important family of trans-membrane signaling proteins and are therapeutic targets in many disorders. The characterization of the structure and conformational dynamics of these receptors present a considerable analytical challenge due to the hydrophobic nature of their transmembrane domains. Recently we have used HDX to probe ligand interactions with the beta-2 adrenergic receptor.

Structural and Chemical Biology of the orphan nuclear receptor LRH-1
Our laboratory has taken a multi-pronged approach to understanding the biology of the orphan nuclear receptor LRH-1 (liver receptor homolog-1). Modulation of LRH-1 activity has been implicated in cancer, cholesterol homeostasis, and in intestinal inflammation. We have developed several HTS assays to facilitate screening for small molecules that positively modulate (agonize) or negatively modulate (inverse agonize) the activity of the receptor. More importantly, we have developed several functional assays to better understand the potential utility of small molecule modulators of LRH-1 for treatment of cancer, inflammation and metabolic disorders. We have discovered synthetic modulators of LRH-1 that demonstrate a range of activities in various cancer cell lines as well as models of inflammation. Several manuscripts are in preparation describing these studies.

Novel modulators of RORα
Using a unique human nuclear receptor library we have discovered novel modulators of RORα. HDX is being employed for mechanism of action studies and to guide SAR. Read our recent articles in Molecular Pharmacology, JBC, and ACS Chemical Biology and Natrure on synthetic and natural ligands for the RORs.

Education

B.S., Chemistry, Syracuse University, 1985
Ph.D., Chemistry, University of Virginia, 1989

Professional Experience

Professor and Chair, Molecular Therapeutics, 03/07 to present
Director, Translational Research Institute, 06/06 to present
Co-founder, Adipothermics, 08/10
Member of Scripps Florida Steering Committee, 01/07 to present
Member of Pfizer/TSRI Joint Steering Committee, 01/07 to present
Member, Board of Directors, Centre for Drug Research and Development, 08/09 to present
Member, Scientific Advisory Board, ExSAR Corp, NJ, 2004 – present
Professor Biochemistry, Scripps Florida, 05/04 - 3/07
Chief Scientific Officer, ExSAR Corporation, 07/02 - 05/04
Senior Director, Basic Chemistry and Molecular Profiling Proteomics, Merck, 09/01 - 06/02
Director, Basic Chemistry and Molecular Profiling Proteomics, Merck, 05/99 – 09/01
Senior Research Fellow, Molecular Design and Diversity, Merck, 04/96 – 05/99
Research Fellow, Inflammation Research, Merck, 12/91-04/96
Post-Doctoral Fellow, California Institute of Technology 5/90 - 12/91
Associate Scientist, Genentech, Inc. 4/89 - 4/90

Awards & Professional Activities

Dupont Chemistry Fellow, University of Virginia
Dean's Fellow, University of Virginia

Selected References

Soon FF, Ng LM, Zhou XE, West GM, Kovach A, Tan MH, Suino-Powell KM, He Y, Xu Y, Chalmers MJ, Brunzelle JS, Zhang H, Yang H, Jiang H, Li J, Yong EL, Cutler S, Zhu JK, Griffin PR, Melcher K, Xu HE., Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases., Science, 2011, Nov 24. [Epub ahead of print].

Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, Kuruvilla DS, Shin Y, He Y, Bruning JB, Marciano DP, Cameron MD, Laznik D, Jurczak MJ, Schürer SC, Vidović D, Shulman GI, Spiegelman BM, and Griffin PR., Anti-Diabetic Actions of a Non-Agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation, Nature, 2011, 477, 477-81

Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidovic D, Schurer S, Xu J, Wagoner G, Drew PD, Griffin PR, and Burris TP, Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand, Nature, 2011, 472, 491-4.

Lee JM, Lee YK, Mamrosh KL, Busby SA, Griffin PR, Pathak MC, Ortlund EA and Moore DD, Antidiabetic Effects of a Novel Agonist Ligand for the Nuclear Receptor LRH-1, Nature, 2011, 447,506-10.

Devarakonda S, Gupta K, Chalmers MJ, Hunt JF, Griffin PR, Van Duyne GD, Spiegelman BM., Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex. Proc Natl Acad Sci U S A., 2011, 108, 18678-83

Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Wang Y, Busby SA, Pascal BD, Garcia-Ordonez RD, Bruning JB, Istrate MA, Kojetin DJ, Dodge JA, Burris TP and Griffin PR, DNA binding alters coactivator interaction surfaces of the intact VDR–RXR complex, Nat Struct Mol Biol, 2011, 18, 556-63.

West GM, Chien EYT, Katritch V, Gatchalian J, Chalmers MJ, Stevens RC, Griffin PR., Ligand-dependent perturbation of the conformational ensemble for the GPCR beta2 adrenergic receptor revealed by HDX, Structure, 2011, 19, 1424-32

Wright E, Busby SA, Wisecarver S, Vincent J, Griffin PR, Fernandez EJ, Helix 11 dynamics is critical for constitutive androstane receptor activity, Structure, 2011, 19, 37-44,

Busby SA, Kumar N, Kuruvilla DS, Istrate MA, Conkright JJ, Wang Y, Kamenecka TM, Cameron MD, Roush WR, Burris TP, Griffin PR., Identification of a Novel Non-retinoid Pan Inverse Agonist of the Retinoic Acid Receptors, ACS Chem Biol., 2011, 17, 618-27.

Heidebrecht T, Christodoulou E, Chalmers MJ, Jan S, Ter Riet B, Grover RK, Joosten RP, Littler D, van Luenen H, Griffin PR, Wentworth P Jr, Borst P, Perrakis A., The structural basis for recognition of base J containing DNA by a novel DNA binding domain in JBP1, Nucleic Acids Res., 2011 39, 5715-5728.

Willis S and Griffin PR, Mutual Information identifies sequence positions conserved within the nuclear receptor superfamily: approach reveals functionally important regions for DNA binding specificity, NURSA, 2011, Feb 25;9:e001.

Chalmers MJ, Busby SA, Pascal BD, West GM and Griffin PR, Differential hydrogen/deuterium exchange mass spectrometry analysis of protein-ligand interactions, Expert Rev Proteomics, 2011, 8, 43-59

Istrate MA, Spicer TP, Wang Y, Bernard JA, Helvering LM, Bocchinfuso WP, Richardson TI, Zink R, Kumar N, Montrose-Rafizadeh C, Dodge JA, Hodder P and Griffin PR, Development of an HTS-Compatible Assay for Discovery of RORα Modulators Using AlphaScreen Technology, J Biomol Screen, 2011, 16, 183-91.

Vidović D, Busby SA, Griffin PR, Schürer SC, A combined ligand- and structure-based virtual screening protocol identifies submicromolar PPARγ partial agonists, ChemMedChem, 2011, 6, 94-103.

Southern MR and Griffin PR, A Java API for working with PubChem datasets, Bioinformatics, 2011, 27, 741-2

Choi JH, Banks AS, Estall JL, Kajimura S, Boström P, Laznik D, Ruas JL, Chalmers MJ, Kamenecka TM, Blüher M, Griffin PR, Spiegelman BM, Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5, Nature, 2010, 466, 451-6.

Kumar N, Kojetin DJ, Solt LA, Kumar KG, Nuhant P, Duckett DR, Cameron MD, Butler AA, Roush WR, Griffin PR, Burris TP., Identification of SR3335 (ML-176): A Synthetic RORα Selective Inverse Agonist, ACS Chem Biol. 2010 Dec 6. [Epub ahead of print]

Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Garcia-Ordonez RD, Pascal BD, Burris TP, Dodge JA and Griffin PR, Hydrogen/Deuterium Exchange Reveals Distinct Agonist/Partial Agonist Receptor Dynamics within the intact Vitamin D Receptor/Retinoid X Receptor Heterodimer, Structure, 2010, 18, 1332-41

Wang Y, Kumar N, Nuhant P, Cameron MD, Istrate MA, Roush WR, Griffin PR, Burris TP Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and RORgamma, ACS Chemical Biology, 2010, In Press (on-line)

Chalmers MJ, Pascal BD, Willis S, Zhang J, Iturria SJ, Dodge JA, and Griffin PR, Methods for the analysis of high precision differential hydrogen-deuterium exchange data, Int. J. Mass Spectrom., 2010, In Press (on-line)

Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Garcia-Ordonez R, Burris TP, and Griffin PR, The benzenesulfoamide T0901317 is a novel RORalpha/gamma inverse agonist, Mol Pharmacol. 2010, 77, 228-36.

Solt LA, Griffin PR and Burris TP Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics, Current Opin Lipidol, 2010, 21, 204-11

Wang Y, Kumar N, Crumbley C, Griffin PR and Burris TP A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol), Biochim Biophys Acta. 2010, 1801, 917-923.

Kumar N, Solt LA, Wang Y, Rogers PM, Bhattacharyya G, Kamenecka TM, Stayrook KR, Crumbley C, Floyd ZE, Gimble JM, Griffin PR and Burris TP Regulation of adipogenesis by natural and synthetic REV-ERB ligands, Endocrinology, 2010, 151, 3015-25.

Zhang X, Chien EYT, Chalmers MJ, Pascal BD, Gatchalian J, Stevens RC, and Griffin PR, Dynamics of the beta2-adrenergic G-protein coupled receptor revelaed by hydrogen/deuterium exchange, Analytical Chem. 2010, 82, 1100-8.

Wang Y, Kumar N, Solt LA, Richardson TI, Helvering LM, Crumbley C, Garcia-Ordonez RD, Stayrook KR, Zhang X, Novick S, Chalmers MJ, Griffin PR, Burris TP., Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands., J Biol Chem., 2010, 285, 5013-25.

Dai S., Burris TP, Dodge JA., Montrose-Rafizadeh C., Wang Y., Pascal B., Chalmers MJ, and Griffin PR, Unique ligand binding patterns between estrogen receptor α and β revealed by hydrogen/deuterium exchange, Biochemistry, 2009, 48, 9668-76.

Pascal BD, Chalmers MJ, Busby SA, Griffin PR, HD desktop: an integrated platform for the analysis and visualization of H/D exchange data, J Am Soc Mass Spectrom. 2009, 20, 601-10.

Avvaru BS, Busby SA, Chalmers MJ, Griffin PR, Venkatakrishnan B, Agbandje-McKenna M, Silverman DN, McKenna R, Apo-human carbonic anhydrase II revisited: implications of the loss of a metal in protein structure, stability, and solvent network, Biochemistry, 2009, 48, 7365-72.

Lauer-Fields JL, Chalmers MJ, Busby SA, Minond D, Griffin PR, Fields GB., Identification of specific hemopexin-like domain residues that facilitate matrix metalloproteinase collagenolytic activity, J Biol Chem., 2009, 284, 24017-24.

Noël R, Song X, Jiang R, Chalmers MJ, Griffin PR, Kamenecka TM., Efficient methodology for the synthesis of 3-amino-1,2,4-triazoles, J Org Chem, 2009, 74, 7595-7.

Dai, S.Y., Chalmers, M.J., Bruning, J., Bramlett, K.S., Osborne, H.E., Montrose-Rafizadeh, C., Barr, R.J., Wang, M., Burris, T.P., Dodge, J.A., Griffin, P.R., Prediction of the tissue-specificity of selective estrogen receptor modulators using a single biochemical method. Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 7171-.

Madoux F, Li X, Chase P, Zastrow G, Cameron MD, Conkright JJ, Griffin PR, Thacher S, Hodder P.,
Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening, Mol Pharmacol, 2008, 73, 1776-84.

Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He Y, Nettles KW, Griffin PR., Partial agonists activate PPARgamma using a helix 12 independent mechanism, Structure, 2007, 15, 1258-71.

Links

Company Ember is launched and website is live.

Nat Struct Mol Biol. 2012 Apr 15. doi: 10.1038/nsmb.2279. [Epub ahead of print]

Scientists Establish New Class of Anti-Diabetic Compound

NIH Research Matters: Designing New Diabetes Drugs

Patrick Griffin and Paul Kenny Awarded Grant to Create National Anti-Addiction Network

Scripps Florida is Awarded Grant to Create National Anti-Addiction Network

Bicoastal Team Pinpoints Shape-Shifting Mechanism Critical to Protein Signaling

Building a Bridge from Basic Science to New Therapies

The Scripps Research Molecular Screening Center