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- PDB-9vlg: Structure of human alpha-2/delta-1 with crisugabalin -

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Basic information

Entry
Database: PDB / ID: 9vlg
TitleStructure of human alpha-2/delta-1 with crisugabalin
ComponentsIsoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1
KeywordsMEMBRANE PROTEIN / Complex / Alpha-2/delta-1 / Crisugabalin
Function / homology
Function and homology information


regulation of membrane repolarization during action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes ...regulation of membrane repolarization during action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / regulation of calcium ion transport / neuronal dense core vesicle / voltage-gated calcium channel activity / presynaptic active zone membrane / sarcoplasmic reticulum / GABA-ergic synapse / cellular response to amyloid-beta / calcium ion transport / extracellular exosome / metal ion binding / plasma membrane
Similarity search - Function
VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / : / von Willebrand factor type A domain / VWFA domain profile. / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
: / Voltage-dependent calcium channel subunit alpha-2/delta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsWang, J. / Chen, Z. / Gou, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Chem Inf Model / Year: 2025
Title: Structural and Computational Insights into the Mechanism of the Superior Pharmacological Activity of Crisugabalin: A Third-Generation Cavαδ1 Ligand.
Authors: Zhaoqiang Chen / Xiaoli Gou / Qingyuan Meng / He Li / Yao Li / Zongjun Shi / Xinxin Li / Ju Wang /
Abstract: Crisugabalin, a recently approved third-generation GABA analogue with a unique cage-like tricyclic scaffold, shows superior efficacy and safety over pregabalin and mirogabalin for treating ...Crisugabalin, a recently approved third-generation GABA analogue with a unique cage-like tricyclic scaffold, shows superior efficacy and safety over pregabalin and mirogabalin for treating neuropathic pain. Through integrated biophysical, structural, and computational approaches, we elucidate the molecular basis of its enhanced pharmacological profile. Dissociation kinetic studies revealed that crisugabalin exhibited the slowest dissociation kinetics from the αδ1 subunit (τ = 32.05, 80.00, 111.11 min for pregabalin, mirogabalin, and crisugabalin) but the fastest dissociation from the αδ2 subunit (τ = 8.70, 16.39, 5.78 min for pregabalin, mirogabalin, and crisugabalin). Cryo-EM structures demonstrated crisugabalin's superior binding affinity for αδ1 over gabapentin and l-leucine, driven by enhanced hydrogen bonding and hydrophobic contacts, alongside volumetric expansion of the l-leucine binding pocket. Molecular dynamics (MD) simulations identified significantly more persistent hydrogen bonding by crisugabalin (66.3% average occupancy) relative to pregabalin (28.3%). Random Acceleration Molecular Dynamics (RAMD) simulations revealed that ligand dissociation primarily proceeds via Pathway A (along the β2, β3, and β1 segments), and τRAMD calculations correctly ranked the ligand residence times, yielding values of 0.18 ns for pregabalin and 2.88 ns for crisugabalin. Furthermore, the binding free energies for pregabalin, mirogabalin, and crisugabalin were -21.64, -31.30, and -34.99 kcal/mol, calculated by MM/GBSA. The decomposition of the binding free energy components revealed that crisugabalin exhibits a dual-action mechanism characterized by enhanced hydrophobic interactions (-28.46 kcal/mol) and favorable entropic contributions (3.03 kcal/mol). This unique binding behavior stems from its cage-like tricyclic scaffold, an unprecedented substructure in drug molecules. These findings establish the cage-like tricyclic motif as a novel pharmacophore that simultaneously optimizes binding entropy and enthalpy, providing a blueprint for next-generation voltage-gated calcium channel modulators. MD, τRAMD, and MM-GBSA used in this study are powerful computational tools for rational drug design, particularly for optimizing compounds with prolonged target residence times.
History
DepositionJun 25, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 7, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jan 7, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,8268
Polymers120,9911
Non-polymers2,8367
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Isoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel subunit alpha-2/delta-1


Mass: 120990.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA2D1, CACNL2A, CCHL2A, MHS3 / Production host: Homo sapiens (human) / References: UniProt: P54289
#2: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Chemical ChemComp-A1ESQ / Crisugabalin


Mass: 209.285 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H19NO2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of human alpha-2/delta-1 with crisugabalin / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

MicroscopyModel: FEI/PHILIPS CM300FEG/HE
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 226483 / Symmetry type: POINT

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