Linking partial and non-agonist induced dynamics to PPAR gamma functions

Summary

Principal Investigator: TRAVIS SHANE HUGHES
Abstract: DESCRIPTION (provided by applicant): The currently prescribed insulin sensitizing drugs, (the full agonists rosiglitazone and pioglitazone), bind to peroxisome proliferators-activated receptor PPAR, a transcription factor) and improve maintenance of normal blood sugar levels, which helps prevent the long-term complications of diabetes, including heart disease and stroke for many of the 25 million diabetic Americans. The anti-diabetic effects of PPAR binding drugs are more durable (prevent diabetes progression for a longer time) and more effective than other drugs such as metformin and glyburide making PPA interacting drugs a valuable treatment for diabetes. However use of these drugs is limited because they cause increased bone fracture in women, weight gain, heart failure and edema. Effective PPAR targeted anti-diabetics with less unwanted effects are needed. PPAR is a transcription factor that interacts with many other proteins to carry out its effects, it interacts with these other proteins on its surface. Many of these interactions depend on a particular ligand being present in the large and hydrophobic PPAR ligand binding pocket. Somehow, binding of ligand changes the structure and/or dynamics of PPAR's interacting surfaces to favor or disfavor interaction with these partners (i.e. co regulators and heterodimerization partner, retinoid X receptor, RXR). This unique ligand induced (or ligand free) PPAR/partner complex increases or decreases the expression of many genes which leads to ligand specific in vivo effects. PPAR crystal structures bound to many different kinds of ligands, both alone and mated with RXR, co regulator proteins and DNA are very similar and do not explain the functional differences observed for different classes of PPAR ligands. We hypothesize that adding movement information to these crystal structures will help correlate PPAR regions and movements with in vivo effects of the distinct classes of PPAR ligands. This correlation map could then be used to drive more effective PPAR drug development. We have evidence that different ligand classes (full, partial and non agonists) can indeed be differentiated by the dynamics they induce. We have found that a PPAR binding non-agonist and two partial agonists all bind PPAR in at least two distinct orientations, while the ful agonist does not. Furthermore our PPAR movement data suggest a novel mechanism for partial agonism in PPAR. Connection of PPAR structure and movement to functional effects will help improve design of novel PPAR drugs with better separation of unwanted effects (e.g. heart failure) from wanted effects (i.e. anti-diabetic efficacy, anti-inflammation). This will improve diabetes treatment and open up possibilities for PPAR targeted therapies for atherosclerosis and autoimmune disorders.
Funding Period: 2012-09-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α
    Sathish Srinivasan
    Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA
    Nat Chem Biol 9:326-32. 2013
  2. pmc An alternate binding site for PPARγ ligands
    Travis S Hughes
    Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA
    Nat Commun 5:3571. 2014
  3. ncbi Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network
    Jerome C Nwachukwu
    Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States
    elife 3:e02057. 2014
  4. pmc Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist
    Edna Matta-Camacho
    From the Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33418 and
    J Biol Chem 289:20054-66. 2014

Detail Information

Publications4

  1. pmc Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α
    Sathish Srinivasan
    Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA
    Nat Chem Biol 9:326-32. 2013
    ..Thus, ligand dynamics directs unique signaling pathways and reveals a new role of the DBD in allosteric control of ERα-mediated signaling...
  2. pmc An alternate binding site for PPARγ ligands
    Travis S Hughes
    Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA
    Nat Commun 5:3571. 2014
    ..These findings expand our understanding of PPARγ activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ activity without competing with endogenous ligands. ..
  3. ncbi Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network
    Jerome C Nwachukwu
    Department of Cancer Biology, The Scripps Research Institute, Jupiter, United States
    elife 3:e02057. 2014
    ..DOI: http://dx.doi.org/10.7554/eLife.02057.001. ..
  4. pmc Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist
    Edna Matta-Camacho
    From the Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33418 and
    J Biol Chem 289:20054-66. 2014
    ....

Research Grants31

  1. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  2. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  3. Adiponectin Actions on the Monocyte to Reduce Atherosclerosis
    Rajendra K Tangirala; Fiscal Year: 2013
    ..abstract_text> ..
  4. STUDIES OF ORGAN TRANSPLANTATION IN ANIMALS AND MAN
    Arthur J Matas; Fiscal Year: 2013
    ..2. To maximize rehabilitation. The focus here is on minimizing complications and maximizing quality of life. ..
  5. Development of iPS Cells for Treatment of Hemoglobinopathies
    Yuet Wai Kan; Fiscal Year: 2013
    ..The science in the Projects will be augmented by an administrative (Core A) and 2 scientific Cores: Core B: Cell and Molecular Biology, and Core C: Cell Transplantation and Analysis. ..
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  7. The role of smooth muscle PPAR gamma in neointima formation
    SETH BERNAT FURGESON; Fiscal Year: 2013
    ..In Aim Three, we will determine which agent can reduce neointima size the greatest after wire injury. ..
  8. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  9. A Novel Therapy for Restricted Induction of Tolerance to Treat Diabetes Mellitus
    Kanneganti Murthy; Fiscal Year: 2013
    ....
  10. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  11. PPAR-gamma and Vascular Lesion Formation
    Yuqing Eugene Chen; Fiscal Year: 2013
    ....
  12. The Role of PPARgamma in Lung Cancer Progression and Metastasis
    Howard Li; Fiscal Year: 2013
    ..Such an environment maximizes the potential for the applicant to establish a scientific niche from which an academic career can be constructed. ..
  13. Discovery of tissue-selective, nonhypercalcemic VDR modulators for RA treatment
    Duane D Miller; Fiscal Year: 2013
    ..Success in developing such agents will not only have high impact for RA, but will also have significant impact in treating many other autoimmune diseases. ..
  14. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  15. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  16. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  17. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  18. Effectiveness of Second Line Hypoglycemic Medications Among Veterans
    Christianne Roumie; Fiscal Year: 2013
    ..The research team is poised to conduct a rigorous study on the safety and clinical effectiveness of second line therapies for DM. ..
  19. GPCR Network
    Raymond C Stevens; Fiscal Year: 2013
    ..Based on the experience of the CMPD investigators, preference will be for human or eukaryotic membrane proteins to maximally leverage the CMPD capabilities. ..
  20. Functional Genetics of COPD
    Edwin K Silverman; Fiscal Year: 2013
    ..resistant Inbred strains which are tested with long-term cigarette smoke exposure. We anticipate that these studies will provide insight into the pathways and mechanisms for COPD susceptibility...
  21. OBESITY, ADIPOGENESIS, AND LIPID LIGANDS
    Clay F Semenkovich; Fiscal Year: 2013
    ..Identifying novel pathways for altering the function of fat cells has the potential to improve the metabolic milieu of obesity and treat obesity-associated diseases. ..
  22. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
  23. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..