title: Structure-activity relationships of ω-Agatoxin IVA in lipid membranes.
abstract: To analyze structural features of ω-Aga IVA, a gating modifier toxin from spider venom, we here investigated the NMR solution structure of ω-Aga IVA within DPC micelles. Under those conditions, the Cys-rich central region of ω-Aga IVA still retains the inhibitor Cys knot motif with three short antiparallel β-strands seen in water. However,15N HSQC spectra of ω-Aga IVA within micelles revealed that there are radical changes to the toxin's C-terminal tail and several loops upon binding to micelles. The C-terminal tail of ω-Aga IVA appears to assume a β-turn like conformation within micelles, though it is disordered in water. Whole-cell patch clamp studies with several ω-Aga IVA analogs indicate that both the hydrophobic C-terminal tail and an Arg patch in the core region of ω-Aga IVA are critical for Cav2.1 blockade. These results suggest that the membrane environment stabilizes the structure of the toxin, enabling it to act in a manner similar to other gating modifier toxins, though its mode of interaction with the membrane and the channel is unique.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea.
authors.forename: Jae Ha
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea.
authors.forename: Hoi Jong
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences and Institute of Neuroscience, Tokushima Bunri University, 1314-1 Shido, Sanuki-shi, Kagawa, 769-2193, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Konishi
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, Republic of Korea.
authors.forename: Ha Hyung
authors.initials: HH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea. Electronic address: zeeyong@gist.ac.kr.
authors.forename: Zee-Yong
authors.initials: ZY
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea. Electronic address: jikim@gist.ac.kr.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
mesh_terms: D000818:Animals; D001665:Binding Sites; D020864:Calcium Channels, N-Type / Q000737:chemistry* / Q000648:ultrastructure*; D002462:Cell Membrane / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008968:Molecular Conformation; D011485:Protein Binding; D011689:Purkinje Cells / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D020867:omega-Agatoxin IVA / Q000737:chemistry*
chemical_list: D020864:Calcium Channels, N-Type; D008051:Lipid Bilayers; D020867:omega-Agatoxin IVA
keywords: Cav2.1; Gating modifier toxin; ω-Agatoxin IVA