Travis Hughes

Associate Professor

Contact Information

Department:
Bmed Acf
Email:
travis.hughes@umontana.edu
Phone:
(406) 243-2750
Office Hours:

Send me an email or stop by.

Personal Website:
https://www.researchgate.net/profile/Travis_Hughes

Office Address

Bmed Acf
Skaggs Bldg. 478
32 Campus Dr MS 1552
Missoula MT, 59812

Hughes Lab News

11/02/23 Travis visits the Universidad de Talca (Chile) to work with several groups at the Center for Bioinformatics, Simulations and Modelling (CBSM) and attended iCBSM4 in early November.

08/21/23 Welcome Bethany Miller! Bethany is doing a rotation in the lab in her first year in the PSDD PhD program.

07.26.23 Our 1-year pilot project is funded to study condensate formation by nuclear receptors and their cofactors. Congratulations Michelle Nemetchek who drove this application and will do most of the work.

07.22.23 We had our second successful computational biology workshop (CompBioAsia23), this time in Singapore at the National University of Singapore. Thanks to all who made it great! 

06.20.23 Congratulations to Mariah Rayl on receiving the Stella Duncan Fellowship that will support her salary for 1 year!

05.15.23 Congratulations to Connor Abel and Lydia Garrick on receiving Center for Translational Medicine summer undergraduate research fellowships 

12.19.22 Michelle Nemetchek successfully defended her PhD dissertation! Congrats Michelle!

12.10.22 Michelle Nemetchek is awarded a travel grant to the Biophysical Society meeting in San Diego.

12.05.22 Our most recent paper is published in PNAS check it out: https://www.pnas.org/doi/abs/10.1073/pnas.2215333119

08.01.22 We have funding for the next five years to explore biased agonism in nuclear receptors! https://reporter.nih.gov/search/0bds1led6EqBVKmm9iYMDg/project-details/10521737

Dr. Hughes leads a group of 6 graduate students and post-docs along with several undergraduate and high-school students focused on understanding how drugs work using a variety of computational and experimental methods.  He has authored or co-authored 28 research manuscripts that have garnered over 3000 total citations.  Dr. Hughes earned Bachelor’s and Master’s degrees in physics and graduated from the University of Colorado with a Ph.D. in biology in 2008. He has since worked in the protein biophysics and biochemistry field including leading protein redesign efforts at a nascent biotech company in Spain, an NIH-supported fellowship in nuclear receptor biophysics in the lab of Dr. Douglas Kojetin at the Scripps Research Institute in Jupiter Florida, and training in molecular simulation in the lab of Dr. Thomas Cheatham III at the University of Utah. Current major funding for the Hughes lab comes from the National Institutes of Health which supports research in drug design and understanding how nuclear receptors signal at atomic resolution. Dr. Hughes is Co-PI with Dr. Amitava Roy on an National Science Foundation educational grant that supports two annual international computational biology workshops (compbioasia.org). 

 

Courses Taught

Dr. Hughes and Dr. Amitava Roy are Co-PIs on an NSF grant that supports computational biology training: compbioasia.org

Classes I teach and/or coordinate:

PHAR 329 (Microbes and Medicines)

BCH 294 (Biochemistry Seminar: Intro to Biochemistry Faculty Research)

BMED 615 (Molecular Pharmacology)

Classes I teach for 2-3 weeks per course:

PHAR 362 (Pharmaceutical Sciences Lab II)

BCH 581 (Physical Biochemistry) I teach mainly about molecular dynamics

Research Interests

picture of the members of the Hughes lab

 

 

 

 

 

 

 

 

 

 

The Hughes lab does Drug Design in collaboration with medicinal chemists. We also study how drugs change the receptors they bind to using various biochemical and biophysical experimental methods along with molecular dynamics simulations. We connect these drug-induced biophysical changes with functional outcomes in cell culture (e.g. through measurement of transcription). Our primary methods are multidimensional protein NMR, fluorine NMR, computational simulations, isothermal titration calorimetry, time-resolved FRET, fluorescence 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 which aids the development of new therapies with reduced undesired effects. Current work mainly focuses 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 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. Helix 12 was in an "inactive" conformation in one of the structures, 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.

 

 

Lab Members

Postdocs:

Michelle Nemetchek uses 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 (who was a PhD student in the Hughes lab) 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". Michelle was the lead author of our recent paper in PNAS: A structural mechanism of nuclear receptor biased agonism.

 

 

Biochemistry and Biophysics Graduate Students:

Mariah Rayl is a 5th year Ph.D. student using Molecular simulations and RNAseq (including the cell culturing part!) to define the acute effects of PPARγ binding drugs on adipocytes and connect those effects to protein structural states.

 

 

 

Reece Lott (Biochemistry and Biophysics Ph.D. student) who started volunteering in the lab in January 2022 as un undergraduate. He is currently optimizing purification of FXR and understanding biased agonism.

Nicholas O'Connor (Biochemistry and Biophysics Ph.D. student). Nick joined the lab in April 2023 and is currently working on purification of coregulator intrinsically disordered regions and preparing samples using HDX-MS to understand biased agonism in PPARγ.

Pharmaceutical Sciences and Drug Design Graduate Students:

Andrew Voss first joined the lab doing research for credit as an undergraduate in Biochemistry. In the Spring of 2022 Andy started in the lab as a Pharmaceutical Sciences and Drug Design Graduate Student (Joint with Philippe Diaz lab). Andy is designing synthesizable small molecules that bind PPARγ and then using molecular dynamics to identify candidates with desired binding modes and then actually synthesizing promising candidates. Andy then plans on testing the effect of these ligands on the structural ensemble (i.e., shape and movement) of PPARγ and their effect on coregulator binding. 

 

Elizabeth Sather is a Ph.D. student who uses simulations, NMR, and fluorescence anisotropy to investigate structure-function properties of several nuclear receptors. She is currently on leave to help her family.

 

 

 

Undergraduates and PharmD student volunteers:

Lydia Garrick is a Biochemistry undergraduate who has volunteered in the lab since Fall 2022 and is helping with coregulator IDR condensate/aggregate characterization and general protein purification.

Stefan Meinken and Connor Abel (PharmD students) started volunteering in the lab Spring 2023. They plan on pursuing a PharmD/MS and are purifying nuclear receptor coregulator receptor interaction domains from bacteria and investigating transcriptional control of a unique PPAR promoter in cells.

Lab Alumni:

Postdocs:

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 now works for a biotech company. 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 the Identification of Significant Events in Molecular Dynamics Simulations) and is contributed to multiple projects involving simulations. (2017-2020).

Undergraduates:

Keri Nauman, a Biochemistry student, joined the lab January 2018 and worked on protein purification and biochemical assays until Fall 2018. 

Graduate Students:

Ian Chrisman graduated with a PhD in December 2018. He used protein crystallization, 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. Dr. Philippe Diaz and Dr. Hughes jointly advised Trey.

Vikash Kumar graduated with a Master's degree from the Biochemistry and Biophysics program in May 2021. He currently teaches Chemistry in India.

PharmD Students:

Elliot Littman and Nina Borzoni (currently finishing their PharmD degrees)

Projects

Current Funding:

NIH NIDDK R01DK129646 (2022-2027) "Structural definition of biased agonism in the nuclear receptor PPAR gamma."

IRES Track II: Cross-disciplinary Computational Biology Training
(Travis Hughes and Amitava Roy are Co-PIs on this grant)
NSF IRES Track II Adanced Studies Institute (2020-2022)

 

Past Funding:

NIH NIGMS Junior Investigator Award (CoBRE Phase II: 2019-2022)

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)

Selected Publications

Hughes lab members underlined. 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

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023.
Burris, T. P., de Vera, I. M. S., Cote, I., Flaveny, C. A., Wanninayake, U. S., Chatterjee, A., Walker, J. K., Steinauer, N., Zhang, J., Coons, L. A., Korach, K. S., Cain, D. W., Hollenberg, A. N., Webb, P., Forrest, D., Jetten, A. M., Edwards, D. P., Grimm, S. L., Hartig, S.Lange CA, Richer JK, Sartorius CA, Tetel M, Billon C, Elgendy B, Hegazy L, Griffett K, Peinetti N, Burnstein KL, Hughes TS, Sitaula S, Stayrook KR, Culver A, Murray MH, Finck BN, Cidlowski JA. Pharmacol Rev. 2023 Nov;75(6):1233-1318. doi: 10.1124/pharmrev.121.000436. Epub 2023 Aug 16. Review. PubMed PMID: 37586884; PubMed Central PMCID: PMC10595025

A structural mechanism of nuclear receptor biased agonism.
Nemetchek MD, Chrisman IM, Rayl ML, Voss AH, Hughes TS.
Proc Natl Acad Sci U S A. 2022 Dec 13;119(50):e2215333119. doi: 10.1073/pnas.2215333119. Epub 2022 Dec 5.
 
Heidari Z, Chrisman IM, Nemetchek MD, Novick SJ, Blayo AL, Patton T, Mendes DE, Diaz P, Kamenecka TM, Griffin PR, Hughes TS
Nature Communications 2019 Dec 20;10(1):5825. doi:/10.1038/s41467-019-13768-0
 

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

Affiliations

Graduate Programs

Pharmaceutical Sciences and Drug Design

Biochemistry and Biophysics

Neuroscience

Centers

Center for Biomolecular Structure and Dynamics

 

Honors / Awards

2019 Rho Chi Professor of the Year, Skaggs School of Pharmacy, University of Montana.
2013 Robert M. Sandelman Award for Scientific Excellence, The Scripps Research Institute
2005 Best Should Teach Silver Award, University of Colorado
 

 

 

Travis Hughes

Search Again