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Proc. Natl. Acad. Sci. USA, Dec 17 2024, 121 (51) | https://doi.org/10.1073/pnas.2314011121
Distinct modulation of calcium-activated chloride channel TMEM16A by drug-binding sites
Jae Won Roha,b,c, Heon Yung Geea, Brian Waingerd, Woo Kyung Kimb,e,1, Wook Leef,1, and Joo Hyun Namb,c,d,1
aDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
bChannelopathy Research Center, Dongguk University College of Medicine, Goyang 10326, Republic of Korea
cDepartment of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
dDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
eDepartment of Internal Medicine, Dongguk University Graduate School of Medicine, Goyang 10326, Republic of Korea
fDepartment of Biochemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
1To whom correspondence may be addressed.
aDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
bChannelopathy Research Center, Dongguk University College of Medicine, Goyang 10326, Republic of Korea
cDepartment of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
dDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
eDepartment of Internal Medicine, Dongguk University Graduate School of Medicine, Goyang 10326, Republic of Korea
fDepartment of Biochemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
1To whom correspondence may be addressed.
Abstract
TMEM16A is a calcium-activated chloride channel with significant role in epithelial fluid secretion, sensory transduction, and smooth muscle contraction. Several TMEM16A inhibitors have been identified; however, their binding sites and inhibitory mechanisms remain unclear. Using magnolol and honokiol, the two regioisomeric inhibitors, as chemical probes, we have identified a drug-binding site distinct from the pore region, in TMEM16A, which is described here. With electrophysiology, unbiased molecular docking and clustering, molecular dynamics simulations, and experimental validation with mutant cycle analysis, we show that magnolol and honokiol utilize different drug-binding sites, pore and nonpore pockets. The pore blocker utilizes amino acids crucial for chloride passage, whereas the nonpore blocker allosterically modulates the pore residues to hinder ion permeation. Among 17 inhibitors tested, 11 were pore blockers and 6 were nonpore blockers, indicating the importance of this nonpore pocket. Our study provides insights into drug-binding mechanism in TMEM16A together with a rationale for future drug development.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-11)
- 국내 연구진
- 의약학 > 인체시스템의학
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