Dr. Hughes obtained his PhD at the University of Colorado in 2008 and shortly after led protein redesign efforts at a nascent start-up biotech company in Spain. He then 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) 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. Molecular, Cellular and Developmental Biology
The Hughes lab studies how drugs change the receptors they bind to using various biochemical and biophysical experimental methods along with molecular dynamics simulations. We also are attempting to 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 is mainly focused on one member of this family, PPARγ, which binds the prescription anti-diabetes drugs pioglitazone (Actos) and rosiglitazone (Avandia).
This figure, adapted from data in our recent publication (Nat Commun 10: 5825 2019), gives an example of our work. The top row shows results from accelerated molecular dynamics simulations. In agreement with experiment (19F NMR bottom row), a key helix for PPARγ function, Helix 12, is stabilized into one main conformation by agonist binding. The total sampling time for each simulation was tens of microseconds (9-50 μs). The two apo (no ligand) simulations were started from different crystal structures. In one of the structures, Helix 12 was in an "inactive" conformation, while the other was started with Helix 12 in an orthogonal "active" structure. The active structure has been shown to bind coactivators, while the inactive would not bind coactivators well.
Biochemistry and Biophysics Graduate Students:
Michelle Nemetchek is a Ph.D. student using protein crystallization, NMR, FRET, fluorescence polarization, and cell-based assays to investigate the structural basis of the anti-inflammatory properties of the nuclear receptor PPARγ. Michelle contributed most of the functional data for the publication "Defining a conformational ensemble that directs activation of PPARγ". Michelle also contributed significantly to "Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ".
Mariah Rayl is a Ph.D. student using cell culture, RNAseq, and biochemical and biophysical assays to define the acute effects of PPARγ binding drugs on macrophage and adipocytes and connect those effects to protein structural states.
Vikash Kumar is a Ph.D. student using simulation, NMR, FRET, and fluorescence polarization to structurally define distinct states of several different nuclear receptors.
Pharmaceutical Sciences and Drug Design Graduate Students:
Elizabeth Sather is a Ph.D. student who uses simulations, NMR, and fluorescence anisotropy to investigate structure-function properties of several nuclear receptors.
Andrew Voss first joined the lab doing research for credit as an undergraduate in Biochemistry. After graduation in May 2020, Andy joined the lab as a technician. Andy purifies protein, performs anisotropy experiments, helps screen crystals, and even fixes our instruments!
Dr. Zahra Heidari focused on the simulation of nuclear receptors using conventional molecular dynamics in combination with various enhanced sampling techniques including accelerated molecular dynamics. Dr. Heidari came to the lab with experience in the development of analysis methods for molecular dynamics simulations (e.g. Using Wavelet Analysis To Assist in Identification of Significant Events in Molecular Dynamics Simulations) and is contributed to multiple projects involving simulations. (2017-2020).
Keri Nauman, a Biochemistry student, joined the lab January 2018 and worked on protein purification and biochemical assays until Fall 2018.
Ian Chrisman graduated with a PhD in December 2018. He used protein crystalization, NMR, FRET and fluorescence polarization to gather structural information about the ensemble of structures of the nuclear receptor PPARγ in distinct functional states (i.e. corepressor bound, coactivator bound etc.). Ian is currently a Scientist I at Salubris Biotherapeutics.
Trey Patton graduated with a Master's degree from the Pharmaceutical Sciences and Drug Design program in May 2019. He now is a Research Scientist at a contract research and manufacturing organization. He used simulation and chemical synthesis to rationally design PPARγ binding drugs. Trey was jointly advised by Dr. Philippe Diaz and Dr. Hughes.
NIH NIGMS Junior Investigator Award (CoBRE Phase II: 2019-2021)
IRES Track II: Cross-disciplinary Computational Biology Training
(Co-PI Amitava Roy)
NSF IRES Track II Adanced Studies Institute (2020-2022)
NIH NIGMS Pilot Project Award via the Center for Biomolecular Structure and Dynamics (CoBRE Phase II: 2018-2019)
NIH NIDDK Pathway to Independence Fellow (K99/R00: 2014-2018)
NIH (NIDDK) NRSA Fellowship (F32: 2012-2014)
American Heart Association Post-doctoral Fellow (2012)
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
Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1.
de Vera, I. M. S., Munoz-Tello, P., Zheng, J., Dharmarajan, V., Marciano, D. P., Matta-Camacho, E., Giri, P. K., Shang, J., Hughes, T. S., Rance, M., Griffin, P. R. & Kojetin, D. J.
Structure (2019). doi:10.1016/j.str.2018.10.002
Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ.
Shang, J., Brust, R., Mosure, S. A., Bass, J., Munoz-Tello, P., Lin, H., Hughes, T. S., Tang, M., Ge, Q., Kamenekca, T. M. & Kojetin, D. J.
Elife 7, 11–15 (2018).
A structural mechanism for directing corepressor-selective inverse agonism of PPARγ.
Brust R, Shang J, Fuhrmann J, Mosure SA, Bass J, Cano A, Heidari Z, Chrisman IM, Nemetchek MD, Blayo AL, Griffin PR, Kamenecka TM, Hughes TS, Kojetin DJ.
Nature Communications. 2018 Nov 8;9(1):4687. PMID: 30409975
Defining a conformational ensemble that directs activation of PPARγ.
Chrisman IM, Nemetchek MD, de Vera IMS, Shang J, Heidari Z, Long Y, Reyes-Caballero H, Galindo-Murillo R, Cheatham TE 3rd, Blayo AL, Shin Y, Fuhrmann J, Griffin PR, Kamenecka TM, Kojetin DJ, Hughes TS.
Nature communications. 2018;9(1):1794. PMID: 29728618
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
Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.
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.
Nature communications. 2015; 6:8013. PMID: 26289479
Deconvolution of Complex 1D NMR Spectra Using Objective Model Selection.
Hughes TS, Wilson HD, de Vera IM, Kojetin DJ.
PloS one. 2015; 10(8):e0134474. PMID: 26241959
Pharmacological repression of PPARγ promotes osteogenesis.
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.
Nature communications. 2015; 6:7443. PMID: 26068133
Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist.
Matta-Camacho E, Banerjee S, Hughes TS, Solt LA, Wang Y, Burris TP, Kojetin DJ.
The Journal of biological chemistry. 2014; 289(29):20054-66. PMID: 24872411
Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network.
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.
eLife. 2014; 3:e02057. PMID: 24771768
An alternate binding site for PPARγ ligands.
Hughes TS, Giri PK, de Vera IM, Marciano DP, Kuruvilla DS, Shin Y, Blayo AL, Kamenecka TM, Burris TP, Griffin PR, Kojetin DJ.
Nature communications. 2014; 5:3571. PMID: 24705063
Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α.
Srinivasan S, Nwachukwu JC, Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ,
Katzenellenbogen JA, Nettles KW.
Nature chemical biology. 2013; 9(5):326-32. PMID: 23524984
Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.
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.
Nature. 2012; 485(7396):62-8. PMID: 22460951
Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism.
Hughes TS, Chalmers MJ, Novick S, Kuruvilla DS, Chang MR, Kamenecka TM, Rance M, Johnson BA, Burris TP, Griffin PR, Kojetin DJ.
Structure (London, England : 1993). 2012; 20(1):139-50. PMID: 22244763
Pharmaceutical Sciences and Drug Design