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Structure of human Cav2.2 channel blocked by the painkiller ziconotide

Abstract

The neuronal-type (N-type) voltage-gated calcium (Cav) channels, which are designated Cav2.2, have an important role in the release of neurotransmitters1,2,3. Ziconotide is a Cav2.2-specific peptide pore blocker that has been clinically used for treating intractable pain4,5,6. Here we present cryo-electron microscopy structures of human Cav2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Cav2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Cav2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Cav channels.

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Fig. 1: Specific pore blockade of Cav2.2 by ziconotide.
Fig. 2: Cytosolic segments unique to Cav2 in the II–III linker.
Fig. 3: VSDII in a down state.
Fig. 4: The down conformation of VSDII is stabilized by several intracellular segments and a bound PIP2.

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Data availability

The atomic coordinates and electron microscopy maps for Cav2.2 in complex with ziconotide and alone have been deposited in the PDB with the accession codes 7MIX (with ziconotide) and 7MIY (without ziconotide) and in the Electron Microscopy Data Bank with the codes EMD-23867 (with ziconotide) and EMD-23868 (without ziconotide), respectively. The atomic coordinates of the proteins for structural comparison in this study can be found in the PDB: rabbit Cav1.1 (5GJW), toxin-bound human Nav1.2 (6J8E), toxin-bound NavPaS-1.7 chimera (6NT4), toxin-bound rat Nav1.5 (7K18), Ci-VSP (4G80), HCN1 (6UQF) and KCNQ1 (6V01). Expression plasmids for the Cav2.2 subunits are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank X. Pan for sharing the expression plasmids for the Cav2.2 complex subunits as a gift; X. Fan for critical discussion on cryo-EM data processing; and the cryo-EM facility at Princeton Imaging and Analysis Center. The work was supported by a grant from the NIH (5R01GM130762).

Author information

Authors and Affiliations

Authors

Contributions

N.Y. conceived the project. S.G. and X.Y. together conducted all wet experiments, including molecular cloning, protein purification, cryo-sample preparation and data acquisition. S.G. performed cryo-EM data processing, model building and refinement. All authors contributed to data analysis. N.Y. wrote the manuscript.

Corresponding author

Correspondence to Nieng Yan.

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The authors declare no competing interests.

Additional information

Peer review information Nature thanks Annette Dolphin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Cryo-EM analysis of the human Cav2.2 complex alone and in the presence of ziconotide.

a, Representative electron micrograph and 30 classes of 2D class averages for Cav2.2–ziconotide. The green circles indicate particles in distinct orientations. The box size for the 2D averages is 312 Å. Scale bar, 50 nm. Left, a half view of one micrograph out of 3,384 in total for Cav2.2–ziconotide. b, Workflow for electron microscopy data processing (Methods). c, The gold-standard Fourier shell correlation (FSC) curves for the 3D reconstructions. The graph was prepared in GraphPad Prism. d, FSC curves of the refined model versus the summed map that it was refined against (black); of the model versus the first half map (red); and of the model versus the second half map (green). Z-complex, Cav2.2–ziconotide.

Extended Data Fig. 2 Cryo-EM structure of the human Cav2.2 complex bound with ziconotide.

a, Heat map for local resolutions of the complex. The resolution map was calculated in Relion 3.0 and prepared in Chimera. Top inset, bound ziconotide (labelled as Zi) is well-resolved. Bottom inset, resolution of the β3 subunit, after a focused refinement, allows for reliable model building using the crystal structure of rat β3 (PDB code 1VYU) as a template. b, Overall structure of the complex at an averaged resolution of 3.0 Å. Left, the complex comprises the α1 core subunit (silver), the extracellular α2δ-1 subunit (light pink for α2 and green for δ) and the cytosolic β3 subunit (wheat). The peptide pore blocker ziconotide is coloured brown. The resolved lipid, cholesterol and CHS molecules are shown as black sticks. The bound PIP2 is shown as black ball-and-sticks. Sugar moieties are shown as thin sticks. Right, surface presentation of the structure. The four repeats are coloured grey, cyan, yellow, and pale green. The III–IV linker and the CTD are coloured orange and pale purple, respectively.

Extended Data Fig. 3 Electron microscopy densities for representative segments of Cav2.2–ziconotide.

a, Electron microscopy maps for representative segments in α1 and β3. The densities for the β3 segments are from focused refinement, and the others are from the overall map. All the densities shown are contoured at 4σ. b, The electron microscopy map for ziconotide. c, Electron microscopy densities for the bound Ca2+ ion and surrounding residues in the selectivity filter. The maps were prepared in PyMol.

Extended Data Fig. 4 Lipids resolved in the structures.

a, A PIP2 molecule binds to VSDII in both structures. All the densities shown are contoured at 3σ. b, The densities for the resolved cholesterol (Cho) and CHS molecules in Cav2.2–ziconotide. c, Lipids resolved in the structure of Cav2.2–ziconotide. The α1 subunit are shown in two opposite side views. The numbering for cholesterol and CHS is consistent with that in b. Two phospholipids are also resolved and assigned as phosphatidylethanolamine (PE).

Extended Data Fig. 5 Structural comparison of the Cav1.1 and Cav2.2 channel complexes.

a, Superimposition of the overall structures of human Cav2.2 (apo) and rabbit Cav1.1 (PDB code 5GJW). For visual clarity, the γ subunit in the endogenous Cav1.1 complex is not shown. The conformational shift of VSDII from Cav1.1 (wheat) to Cav2.2 (blue) is indicated by the blue arrow. b, Identical structures of the α2δ-1 subunit in the two channel complexes. A detailed structural description of the α2δ-1 subunit can be found in a previous publication18. c, Structural differences of the ECLs between Cav1.1 and Cav2.2. An extracellular view of the superimposed α1 subunits in the two channels is shown.

Extended Data Fig. 6 Conformational shifts of Cav2.2 upon ziconotide binding.

a, ECLI does not participate in ziconotide coordination. An extracellular view perpendicular to that in Fig. 1c is shown. b, Slightly different mode of action of KIIIA for Nav1.226. Lys7 in KIIIA directly blocks the outer mouth of the selectivity filter vestibule of Nav1.2 (PDB code 6J8E), in a manner similar to a cork. Ziconotide lacks an equivalent basic residue. c, Relative shift of α2δ-1 between apo (blue) and ziconotide-bound Cav2.2 (domain-coloured) when the two structures are superimposed relative to the α1 subunit. The rest of the complex remains identical except for ECLIII. d, Concerted motion of α2δ-1 and ECLIII of α1. The α2δ-1 subunit in the two structures can be superimposed with a root mean square deviation of 0.28 Å over 847 Cα atoms, indicating nearly identical conformations. When the two structures are superimposed relative to α2δ-1, the entire α1 undergoes a relative shift—except for ECLIII, which stays as a rigid body with α2δ-1.

Extended Data Fig. 7 Conformational changes of VSDII and VSDIII between Cav1.1 and Cav2.2.

a, Structural comparison of Cav2.2 VSDII with other VSDs that exhibit down conformations. To make the nomenclature consistent, we define the gating charge residue on the first helical turn of the S4 segment as R1. The PDB accession codes are 6NT4 for VSDIV in the chimeric NavPaS-1.7, 7K18 for toxin-bound VSDIV in rat Nav1.5, 4G80 for the antibody-locked VSD of a voltage-sensitive phosphatase, and 6UQF for the VSD of HCN1 in hyperpolarized conformation. b, Structural comparison of Cav1.1 and Cav2.2 shows a slight rotation of VSDIII around the pore domain. The superimposed structures of the diagonal repeats I and III of Cav1.1 (wheat) and Cav2.2 (domain-coloured) are shown. c, VSDIII remains nearly rigid in these two structures. When the structures of VSDIII in the two channels are individually superimposed, the S4 segment and the gating charge residues align well. d, Marked shift of S4II between Cav1.1 and Cav2.2 when the two structures are compared relative to VSDII. S4II undergoes a combination of spiral sliding and secondary structural transition. S1, S2 and S3 remain nearly unchanged in these two VSDII structures, which suggests a concerted rotation of the other three segments pivoting around S4.

Extended Data Fig. 8 A closed pore domain with one small fenestration.

a, The pore domain is in a closed conformation. Four perpendicular side views of the pore domain are shown. S4–5II is pushed downward as a result of the sliding of S4II. b, Side walls that involve S6II are sealed without fenestration. Side views of the pore domain surface are shown. There is only one fenestration on the interface of repeats III and IV.

Extended Data Fig. 9 A PIP2 molecule may help to stabilize the down conformation of Cav2.2 VSDII.

a, The binding pose for PIP2 is incompatible with an up VSDII. Left, coordination of the head group of PIP2 by Cav2.2. Side local view of VSDII is shown. Right, in an up state of VSDII (as in Cav1.1), R4 and K5 can no longer interact with the PIP2 head group, and S4–5II directly clashes with PIP2. Structures of Cav1.1 and Cav2.2 are superimposed relative to the α1 subunit and Cav2.2 is omitted to highlight the relative position of PIP2 to Cav1.1. b, The hydrophobic tails of PIP2 interact extensively with multiple segments in repeats II and III. Hydrophobic residues on segments S3 to S6 in repeat II and S5 and S6 in repeat III contact the two tails of PIP2. c, The PIP2 molecule in the Kv channel KCNQ1 is bound at a similar, but lower, position. The PDB code for the KCNQ1 structure is 6V01. d, Rearrangement of the interface of VSDII and pore domain between Cav2.2 and Cav1.1. Cav1.1 is coloured with the same scheme as for Cav2.2. Alternative sets of hydrophobic residues between the gating charge residues on S4II are used for interacting with S5III in Cav1.1 and Cav2.2 as a result of the rotation of S4II. The sequence numbers for corresponding VSDII residues in these two channels differ by 50, and those for S5III residues differ by 354. As labelled in the parentheses, Val1298 and Phe1292 on the S5III segment of Cav2.2 are at loci corresponding to Cys944 and Leu938 in Cav1.1, respectively.

Extended Data Table 1 Statistics for data collection and structural refinement

Supplementary information

Supplementary Figure 1

Sequence alignment of the α1 subunit of human Cav channels and rabbit Cav1.1.

Reporting Summary

Video 1 Overall structure of the Cav2.2 channel complex

The complex is coloured the same as in Fig. 1a.

Video 2 Conformational changes of the α1 subunits between Cav2.2 and Cav1.1

The morph was generated in PyMol using structures of human Cav2.2 and rabbit Cav1.1 (PDB code: 5GJW) as the first and end frames. For visual clarity, the cytosolic segments, which are poorly resolved in Cav1.1, are omitted.

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Gao, S., Yao, X. & Yan, N. Structure of human Cav2.2 channel blocked by the painkiller ziconotide. Nature 596, 143–147 (2021). https://doi.org/10.1038/s41586-021-03699-6

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