Kevin J. Phillips, Ph.D.
Ph.D. Harvard University, Cambridge, MA
Postdoctoral Associate, University of California at San Francisco, USA
Dr. Phillips pursued his doctoral research at Harvard University, working in the the field of chemical biology. He then moved to San Francisco for postdoctoral training under the direction of John Baxter and Robert Fletterick at the University of California at San Francisco where he pursued structural studies of nuclear hormone receptors. In 2008, Dr. Phillips moved from UCSF to The Methodist Hospital Research Institute.
The three key areas of Dr. Phillips’ research are:
Thyroid hormone action. Obesity, an expanding health problem, tends be accompanied by co-morbitidies that are often referred to as metabolic syndrome. Activation of thyroid hormone receptors (TRs), either by endogenous thyroid hormone or by synthetic TR agonists, elicits catabolic processes that tend to oppose the maladies of metabolic syndrome. Dr. Phillips’ group is working to establish the molecular mechanisms by which the TRs mediate these clinically useful actions that include: the reduction of serum cholesterol and lipid levels, the amelioration of fatty liver disease, improved insulin sensitivity, and fat loss (see below).
Adaptive thermogenesis. A key interest is understanding how TR activation mediates thermogenesis - the conversion of excess energy (such as extra calories or fat) to heat. In work that is ongoing, his group has discovered a novel mechanism by which TR agonists elicit thermogenesis, leading to dramatic fat loss in preclinical models of severe obesity. They are currently working to identify the molecular events that mediate this action and are exploring the beneficial physiological effects that accompany thermogenic induction.
Chemical biology. Based on an improved understanding of TR action, his research also seeks to develop novel chemical probes that target either the TRs themselves or downstream effectors of the TRs. Dr. Phillips’ group is also involved in numerous collaborations in which they provide chemical or structural biology expertise.
Obesity, metabolism, thyroid hormone action, thermogenesis, chemical biology
Rajagopalan S, Teter SJ, Zwart PH, Brennan RG, Phillips KJ, Kiley PJ. Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity. Nat Struct Mol Biol. 2013 May 5. PMID: 23644595.
Lin JZ, Martagón AJ, Hsueh WA, Baxter JD, Gustafsson JÅ, Webb P, Phillips KJ. Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor. Endocrinology. 2012 Dec;153(12):6136-44. PMID: 23087171
Horton LB, Shanker S, Mikulski R, Brown NG, Phillips KJ, Lykissa E, Venkataram Prasad BV, Palzkill T. Mutagenesis of zinc ligand residue Cys221 reveals plasticity in the IMP-1 metallo-ß-lactamase active site. Antimicrob Agents Chemother. 2012 Nov;56(11):5667-77. PMID: 22908171
Liberato MV, Nascimento AS, Ayers SD, Lin JZ, Cvoro A, Silveira RL, Martínez L, Souza PC, Saidemberg D, Deng T, Amato AA, Togashi M, Hsueh WA, Phillips K, Palma MS, Neves FA, Skaf MS, Webb P, Polikarpov I. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) ? activators and pan-PPAR partial agonists. PLoS One. 2012;7(5):e36297. PMID: 22649490
Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira AC, Lu J, Ayers SD, Mottin M, Silveira RL, Souza PC, Mourão RH, Saad MJ, Togashi M, Simeoni LA,Abdalla DS, Skaf MS, Polikparpov I, Lima MC, Galdino SL, Brennan RG, Baxter JD,Pitta IR, Webb P, Phillips KJ, Neves FA. GQ-16, a novel peroxisomeproliferator-activated receptor ? (PPAR?) ligand, promotes insulin sensitization without weight gain. J Biol Chem. 2012 Aug 10;287(33):28169-79. PMID: 22584573
Riu A, Grimaldi M, le Maire A, Bey G, Phillips K, Boulahtouf A, Perdu E, Zalko D, Bourguet W, Balaguer P. Peroxisome proliferator-activated receptor ? is a target for halogenated analogs of bisphenol A. Environ Health Perspect. 2011 Sep;119(9):1227-32. PMID: 21561829
Phillips KJ, de la Peña AH. The Combined Use of the Thermofluor Assay and ThermoQ Analytical Software for the Determination of Protein Stability and Buffer Optimization as an Aid in Protein Crystallization. Curr Protoc Mol Biol. 2011 Apr; Chapter 10:Unit10.28. PMID: 21472694
Martínez L, Nascimento AS, Nunes FM, Phillips K, Aparicio R, Dias SM, Figueira AC, Lin JH, Nguyen P, Apriletti JW, Neves FA, Baxter JD, Webb P, Skaf MS, Polikarpov I. Gaining ligand selectivity in thyroid hormone receptors via entropy. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20717-22. PMID: 19926848
Estébanez-Perpiñá E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ. Structural Insight Into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor. Mol Endocrinol 2007;21:2919. PMID: 17823305
Lawrence MS, Phillips KJ, Liu DR. Supercharging Proteins Can Impart Extraordinary Resilience. J Am Chem Soc. 2007;129:10110. PMID: 17665911
Phillips KJ, Rosenbaum DM, Liu DR. Binding and Stability Determinants of the PPAR? Nuclear Receptor/Coactivator Interface as Revealed by Shotgun Alanine Scanning and In Vivo Selection. J Am Chem Soc. 2006;128:11298. PMID: 17665911
Bittker JA, Phillips KJ, Liu DR. Recent Advances in the In Vitro Evolution of Nucleic Acids. Curr Opin Chem Biol. 2002;6:367. PMID: 12023118