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Structural Investigations of the PH Sensing and Drug Inhibition Mechanisms of Proton Activation
Chloride (PAC) Channel


EMSL Project ID
51236

Abstract

Proton-activation chloride channel (PAC) is a ubiquitously expressed ion channel that is responsible for
the acid-induced chloride current (I Cl,H ) present in mammalian cells. The molecular identity of PAC
channel was discovered early this year by two independent groups. Although initial mutagenesis and
biochemical assay has provided critical information regarding the transmembrane helices (TM)
arrangement and pore-lining residues of PAC, the structural information is currently lacking, hindered a
detailed understanding of the channel function and the gating mechanisms. To fulfill this knowledge
gap, the research plan aims to provide a comprehensive investigation on PAC proton-sensing
mechanisms by solving its structure at different conformational states, including resting state, open
state, and desensitized state. Moreover, the activation of PAC was found to cause acid-induced cell
death, a process underlies many human diseases, such as cancer and ischemic stroke. Therefore,
selective inhibition on PAC possesses great potential as a therapeutic strategy to treat patients with
these pathological conditions. PAC is sensitive to several non-specific chloride channel blockers such
as DIDS, niflumic acid and NPPB. The proposed plan will also study the interaction between PAC and
these inhibitors through structural approaches, which may guide future pharmacological intervention
and drug design for PAC. The

Project Details

Start Date
2019-12-20
End Date
2021-03-17
Status
Closed

Team

Principal Investigator

Juan Du
Institution
Van Andel Research Institute

Co-Investigator(s)

Wei Lu
Institution
Van Andel Research Institute

Team Members

Zheng Ruan
Institution
Van Andel Research Institute

Harry Scott
Institution
Oregon Health & Science University