7W77
cryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA
Summary for 7W77
Entry DOI | 10.2210/pdb7w77/pdb |
EMDB information | 32341 |
Descriptor | Sodium channel subunit beta-1, Sodium channel subunit beta-2, Sodium channel protein type 3 subunit alpha, ... (9 entities in total) |
Functional Keywords | ion channel, drug, antagonist, membrane protein |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 3 |
Total formula weight | 285991.70 |
Authors | |
Primary citation | Li, X.,Xu, F.,Xu, H.,Zhang, S.,Gao, Y.,Zhang, H.,Dong, Y.,Zheng, Y.,Yang, B.,Sun, J.,Zhang, X.C.,Zhao, Y.,Jiang, D. Structural basis for modulation of human Na V 1.3 by clinical drug and selective antagonist. Nat Commun, 13:1286-1286, 2022 Cited by PubMed Abstract: Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development. PubMed: 35277491DOI: 10.1038/s41467-022-28808-5 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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