Structure and Mechanism of a Polymodal TRP Ion Channel Transient receptor potential (TRP) ion channels are crucial for sensory transduction and cellular signaling, and TRP channel dysfunction is associated with a vast array of hereditary and acquired diseases including cancer, chronic pain, hypertension, and neurological disorders. Because of their central roles in physiology and pathophysiology, TRP channels have been intensively studied and are among the most aggressively pursued drug targets. However, advances in our understanding of TRP channel function and therapeutic interventions have been hindered by a lack of three-dimensional high-resolution structural information for most TRP channels. Our long-term goal is to develop structural and biochemical approaches to elucidate molecular mechanisms of TRP channels at the atomic level. By developing new methods to systematically evaluate heterologous expression, purification, and optimization of TRP channel homologs, we have recently crystallized a nearly full-length functional channel and obtained preliminary X-ray diffraction to 4.8 resolution. With this technical breakthrough and further optimization, we are now able to combine X-ray crystallography, single-particle cryo-electron microscopy (cryo-EM), patch-clamp electrophysiology, and site-directed mutagenesis to address fundamental molecular mechanisms. Specifically, we aim to determine high-resolution X-ray and cryo-EM structures of the channel bound with agonists or antagonists, and in complex with membrane lipids that regulate channel activity, and to dissect the underlying mechanisms of disease-associated mutations. Our proposed work will provide X-ray and cryo-EM structures of a TRP channel in multiple functional states and uncover structural and molecular mechanisms. In doing so, we will not only bring fundamental insights into TRP channel function, but also establish a foundation for rational design of new therapeutics for the treatment of many channel-associated diseases.

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Transient receptor potential (TRP) channels play central roles in numerous physiological processes, and TRP channel dysfunction is associated with a variety of human diseases including cancer, chronic pain, hypertension, and neurological disorders. Our proposed structural and functional studies will provide a framework for understanding molecular mechanisms and establish a foundation for developing rational therapies for the treatment of channel-associated diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Silberberg, Shai D
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Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
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Deng, Zengqin; Paknejad, Navid; Maksaev, Grigory et al. (2018) Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms. Nat Struct Mol Biol 25:252-260