Christopher Comer, Dean
Travis Hughes pursued research in instrument design and then atomic force microscopy of an ion channel while obtaining a B.S. and M.S. degree in Physics from Brigham Young University in Utah (2003). He then moved fully toward biology while obtaining his PhD. in the lab of Leslie Leinwand at the University of Colorado at Boulder in the department of Molecular, Cellular and Developmental Biology where he researched gene therapy of the central nervous system using plasmid DNA as a gene delivery vector (2008). After research in protein redesign at a nascent start-up biotech company in Spain he moved on to NIH (NRSA individual fellowship) supported postdoctoral training in the lab of Douglas Kojetin at the Scripps Research Institute in Jupiter Florida. Training at Scripps synthesized previous experience and education in physics and biology as he used protein and fluorine NMR to reveal an allosteric binding site on a well known type II anti-diabetes drug target (PPARγ). Further funding (NIH pathway to independence award, K99/R00) facilitated training in molecular simulation using AMBER in the lab of Thomas Cheatham III in the medicinal chemistry department at the University of Utah. This funding now supports Dr. Hughes' independent research in connecting drug induced biophysical changes in PPARγ with drug induced functional outputs in cells at the University of Montana, where he started as new faculty in January of 2016. Travis is also associated with the Center for Biomolecular Structure and Dynamics, which provides a rich environment for research in protein dynamics.
B.S. Physics, M.S. Physics, Ph.D. MCD Biology
We study how drugs change the receptors they bind to using various biochemical and biophysical experimental methods along with molecular dynamics simulations. We then connect these drug induced biophysical changes with drug induced functional outcomes in cell culture (e.g. through measurement of drug induced changes in transcription). Our primary methods are multidimensional protein NMR, fluorine NMR, computational methods, isothermal titration calorimetry, time-resolved FRET, fluoresence polarization, cell culture and transcriptome analysis. We focus on the nuclear hormone receptor family, which is the molecular target of more than 10% of FDA approved drugs. Our work improves the biophysical understanding of how drugs produce effects in this family, this knowledge aids development of new therapies with reduced undesired effects. Current work focues on one member of this family, PPARγ, which binds the prescription anti-diabetes drugs pioglitazone (Actos) and rosiglitazone (Avandia).
Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA.
de Vera IMS, Zheng J, Novick S, Shang J, Hughes TS, Brust R, Munoz-Tello P, Gardner WJ Jr, Marciano DP, Kong X, Griffin PR, Kojetin DJ.
Structure (London, England : 1993). 2017; 25(10):1506-1518.e4. PMID: 28890360
Probing the Complex Binding Modes of the PPARγ Partial Agonist 2-Chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (T2384) to Orthosteric and Allosteric Sites with NMR Spectroscopy.
Hughes TS, Shang J, Brust R, de Vera IMS, Fuhrmann J, Ruiz C, Cameron MD, Kamenecka TM, Kojetin DJ.
Journal of medicinal chemistry. 2016; 59(22):10335-10341. PMID: 27783520
Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW. Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. Nat Commun. 2015 Aug 20;6:8013. PMID: 26289479 Free full textRelated citations
Marciano DP, Kuruvilla DS, Boregowda SV, Asteian A, Hughes TS, Garcia-Ordonez R, Corzo CA, Khan TM, Novick SJ, Park H, Kojetin DJ, Phinney DG, Bruning JB, Kamenecka TM, Griffin PR. Pharmacological repression of PPARγ promotes osteogenesis.Nat Commun. 2015 Jun 12;6:7443. PMID: 26068133 Free full textCited in PMCRelated citations
Hughes TS, Wilson HD, de Vera IM, Kojetin DJ. Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection.PLoS One. 2015 Aug 4;10(8):e0134474. eCollection 2015. PMID: 26241959 Free full textRelated citations
Matta-Camacho E, Banerjee S, Hughes TS, Solt LA, Wang Y, Burris TP, Kojetin DJ. Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist. J Biol Chem. 2014 Jul 18;289(29):20054-66. Epub 2014 May 28. PMID: 24872411 Free full textCited in PMCRelated citations
Nwachukwu JC, Srinivasan S, Bruno NE, Parent AA, Hughes TS, Pollock JA, Gjyshi O, Cavett V, Nowak J, Garcia-Ordonez RD, Houtman R, Griffin PR, Kojetin DJ, Katzenellenbogen JA, Conkright MD, Nettles KW. Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. Elife. 2014 Apr 25;3:e02057. PMID: 24771768 Free full textCited in PMCRelated citations
Hughes TS, Giri PK, de Vera IM, Marciano DP, Kuruvilla DS, Shin Y, Blayo AL, Kamenecka TM, Burris TP, Griffin PR, Kojetin DJ.An alternate binding site for PPARγ ligands. Nat Commun. 2014 Apr 7;5:3571. PMID: 24705063 Free full textCited in PMCRelated citations
Srinivasan S, Nwachukwu JC, Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ, Katzenellenbogen JA, Nettles KW. Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α. Nat Chem Biol. 2013 May;9(5):326-32. PMID: 23524984 Free full textCited in PMCRelated citations
Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo SH, Takahashi JS, Butler AA, Kamenecka TM, Burris TP. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012 Mar 29;485(7396):62-8. PMID: 22460951 Free full textCited in PMCRelated citations
Hughes TS, Chalmers MJ, Novick S, Kuruvilla DS, Chang MR, Kamenecka TM, Rance M, Johnson BA, Burris TP, Griffin PR, Kojetin DJ. Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism. Structure. 2012 Jan 11;20(1):139-50. PMID: 22244763 Free full textCited in PMCRelated citations
For a complete list of publications see: http://www.ncbi.nlm.nih.gov/sites/myncbi/travis.hughes.1/bibliography/44101010/public/?sort=date&direction=descending
NIH NIDDK Pathway to Independence Fellow (K99/R00: 2014-2018)
NIH (NIDDK) NRSA Fellowship (F32: 2012-2014)
American Heart Association Post-doctoral Fellow (2012)
Phar Sci Research Interests
Molecular pharmacology of a family of ligand activated transcription factors, which are the target of ~10% of FDA approved drugs using biophysical, biochemical and cell biology approaches.
Neuroscience Research Interests
Several prescription ant-diabetes drugs show anti-Alzheimer's activity. We seek to understand the molecular basis of this activity and to develop improved drugs with enhanced effectiveness.
Med Chem Research Interests
Use of computational modeling, biophysical and biochemical methods to guide modification of existing nuclear receptor drugs.
Pharmaceutical Sciences and Drug Design
Biochemistry and Biophysics
Center for Biomolecular Structure and Dynamics