Regulation of transcription activation during cellular development, division and death are tightly regulated in response to intracellular and environmental cues by intricate protein complexes. Such regulation is well represented by the xenobiotic and hypoxia response pathways, where heterodimeric Per-ARNT-SIM (PAS) domain containing transcription factors respond to environmental stress through alterations in protein:protein interactions. In particular, the Aryl hydrocarbon Receptor (AhR) is activated by diverse exogenous and endogenous compounds to induce a conformational response that gates protein recognition. Despite extensive toxicological and cell biological studies of AhR, due to its role in the development and progression of cancer, atherosclerosis, chloracne and sexual development, structural information demonstrating the mechanisms of protein:protein recognition and specificity depending on ligand identity remain largely unknown. Moreover, discerning the role of AhR in human diseases is complicated by seemingly contradictory reports due to cell and tissue type dependent functions and substantial crosstalk with alternative signaling pathways (i.e. estrogen receptor, inflammation response, endocrine system). Structural characterization of AhR activation in response to diverse ligands will aid in delineating direct effects of AhR from indirect effects due to alternative pathway excitation. Of primary importance is determining the conformational landscape induced by AhR agonists and antagonists, and how different ligands direct alternative protein:protein interactions. A molecular understanding of ligand-induced conformational dynamics and subsequent protein recognition can be well characterized using a combination of NMR and X-ray crystallography.

Public Health Relevance

A detailed understanding of ligand-induced conformational states and their role in protein:protein interactions will aid in directing AhR activation and gene regulation. Further, identification of new AhR ligands that select for discrete modes of AhR activation will be of direct therapeutic use in the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM090671-02
Application #
8021775
Study Section
Special Emphasis Panel (ZRG1-F04B-B (20))
Program Officer
Flicker, Paula F
Project Start
2010-02-01
Project End
2011-08-05
Budget Start
2011-02-01
Budget End
2011-08-05
Support Year
2
Fiscal Year
2011
Total Cost
$29,735
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Zoltowski, Brian D; Motta-Mena, Laura B; Gardner, Kevin H (2013) Blue light-induced dimerization of a bacterial LOV-HTH DNA-binding protein. Biochemistry 52:6653-61
Zoltowski, Brian D; Gardner, Kevin H (2011) Tripping the light fantastic: blue-light photoreceptors as examples of environmentally modulated protein-protein interactions. Biochemistry 50:4-16
Zoltowski, Brian D; Nash, Abigail I; Gardner, Kevin H (2011) Variations in protein-flavin hydrogen bonding in a light, oxygen, voltage domain produce non-Arrhenius kinetics of adduct decay. Biochemistry 50:8771-9