Structural basis for CaVα2δ:gabapentin binding

doi:10.1038/s41594-023-00951-7

2023-03-27

Zhou Chen

Abhisek Mondal

Daniel L. Minor *

DOI：10.1038/s41594-023-00951-7

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摘要

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Gabapentinoid drugs for pain and anxiety act on the Ca-V alpha(2)delta-1 and Ca-V alpha(2)delta-2 subunits of high-voltage-activated calcium channels (Ca(V)1s and Ca(V)2s). Here we present the cryo-EM structure of the gabapentin-bound brain and cardiac Ca(V)1.2/Ca-V beta(3)/Ca-V alpha(2)delta-1 channel. The data reveal a binding pocket in the Ca-V alpha(2)delta-1 dCache1 domain that completely encapsulates gabapentin and define Ca-V alpha(2)delta isoform sequence variations that explain the gabapentin binding selectivity of Ca-V alpha(2)delta-1 and Ca-V alpha(2)delta-2. Gabapentinoid drugs are widely used for pain, epilepsy and mental disorders. Chen et al. report the structure of a gabapentin-bound brain and heart calcium channel, revealing the gabapentin binding site and isoform-selective binding determinants.

Keyword:

GATED CALCIUM-CHANNELS

ALPHA(2)DELTA SUBUNITS

GABAPENTIN

PREGABALIN

TRAFFICKING

DRUG

PHARMACOLOGY

EXPRESSION

PHYSIOLOGY

PROTEINS

期刊

Nature Structural and Molecular Biology

IF:

10.1

论文数:

4.8K

被引数:

2.8W

机构

University of California System

学者数:

37.5W

论文数: 33.7W

被引数: 6.6K

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