Structural basis for CaVα2δ:gabapentin binding

Zhou Chen; Abhisek Mondal; Daniel L Minor Jr

doi:10.1038/s41594-023-00951-7

Structural basis for Ca_Vα₂δ:gabapentin binding

Nat Struct Mol Biol. 2023 Jun;30(6):735-739. doi: 10.1038/s41594-023-00951-7. Epub 2023 Mar 27.

Authors

Zhou Chen^#¹, Abhisek Mondal^#¹, Daniel L Minor Jr^{2

3

4

5

6}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
² Cardiovascular Research Institute, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
³ Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁴ California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁵ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁶ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. daniel.minor@ucsf.edu.

^# Contributed equally.

Abstract

Gabapentinoid drugs for pain and anxiety act on the Ca_Vα₂δ-1 and Ca_Vα₂δ-2 subunits of high-voltage-activated calcium channels (Ca_V1s and Ca_V2s). Here we present the cryo-EM structure of the gabapentin-bound brain and cardiac Ca_V1.2/Ca_Vβ₃/Ca_Vα₂δ-1 channel. The data reveal a binding pocket in the Ca_Vα₂δ-1 dCache1 domain that completely encapsulates gabapentin and define Ca_Vα₂δ isoform sequence variations that explain the gabapentin binding selectivity of Ca_Vα₂δ-1 and Ca_Vα₂δ-2.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Calcium Channels* / chemistry
Gabapentin

Substances

Gabapentin
Calcium Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding