α-Conotoxin Vc1.1 Structure–Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain ReplacementClick to copy article linkArticle link copied!
- Xin ChuXin ChuKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, ChinaLaboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, ChinaMore by Xin Chu
- Han-Shen Tae*Han-Shen Tae*E-mail: [email protected]Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, AustraliaMore by Han-Shen Tae
- Qingliang XuQingliang XuKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, ChinaLaboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, ChinaMore by Qingliang Xu
- Tao JiangTao JiangKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, ChinaLaboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, ChinaMore by Tao Jiang
- David J. AdamsDavid J. AdamsIllawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, AustraliaMore by David J. Adams
- Rilei Yu*Rilei Yu*E-mail: [email protected]Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, ChinaLaboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, ChinaInnovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, ChinaMore by Rilei Yu
Abstract
α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1-bound α9α10 nAChR remains unavailable; thus, understanding the structure–activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required. However, Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81, respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second-generation mutants of Vc1.1 [S4 Dab, N9A] and [S4 Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4 Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure–activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.
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