Identification and mechanistic analysis of an inhibitor of the CorC Mg2+ transporter

• Main Authors: Yichen Huang, Kaijie Mu, Xinyu Teng, Yimeng Zhao, Yosuke Funato, Hiroaki Miki, Weiliang Zhu, Zhijian Xu, Motoyuki Hattori
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: iScience
• Subjects: Chemical Compound; Membranes; Structural Biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004221003382

Summary: The CorC/CNNM family of Na+-dependent Mg2+ transporters is ubiquitously conserved from bacteria to humans. CorC, the bacterial CorC/CNNM family of proteins, is involved in resistance to antibiotic exposure and in the survival of pathogenic microorganisms in their host environment. The CorC/CNNM family proteins possess a cytoplasmic region containing the regulatory ATP-binding site. CorC and CNNM have attracted interest as therapeutic targets, whereas inhibitors targeting the ATP-binding site have not been identified. Here, we performed a virtual screening of CorC by targeting its ATP-binding site, identified a compound named IGN95a with inhibitory effects on ATP binding and Mg2+ export, and determined the cytoplasmic domain structure in complex with IGN95a. Furthermore, a chemical cross-linking experiment indicated that with ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC was shifted more toward the inward-facing state of the transmembrane domain. In contrast, IGN95a did not induce such a shift.