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- EMDB-65160: Structure of human alpha-2/delta-1 with crisugabalin -

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Basic information

Entry
Database: EMDB / ID: EMD-65160
TitleStructure of human alpha-2/delta-1 with crisugabalin
Map data
Sample
  • Complex: Structure of human alpha-2/delta-1 with crisugabalin
    • Protein or peptide: Isoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Crisugabalin
KeywordsComplex / Alpha-2/delta-1 / Crisugabalin / MEMBRANE PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsWang J / Chen Z / Gou X
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Chem Inf Model / Year: 2026
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, 2025-
Header (metadata) releaseJan 7, 2026-
Map releaseJan 7, 2026-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65160.png

Downloads & links

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Map

FileDownload / File: emd_65160.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 288 pix.
= 235.872 Å		0.82 Å/pix.
x 288 pix.
= 235.872 Å		0.82 Å/pix.
x 288 pix.
= 235.872 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.819 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.16707972 - 0.35724485
Average (Standard dev.)-0.00030034655 (±0.009367353)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 235.87201 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65160_msk_1.map
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Additional map: cryoSPARC sharpened map

Fileemd_65160_additional_1.map
AnnotationcryoSPARC sharpened map
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Half map: #1

Fileemd_65160_half_map_1.map
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Half map: #2

Fileemd_65160_half_map_2.map
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Sample components

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Entire : Structure of human alpha-2/delta-1 with crisugabalin

EntireName: Structure of human alpha-2/delta-1 with crisugabalin
Components
  • Complex: Structure of human alpha-2/delta-1 with crisugabalin
    • Protein or peptide: Isoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Crisugabalin

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Supramolecule #1: Structure of human alpha-2/delta-1 with crisugabalin

SupramoleculeName: Structure of human alpha-2/delta-1 with crisugabalin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: Isoform 2 of Voltage-dependent calcium channel subunit alpha-2/delta-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 120.990766 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HHHHHHHHWS HPQFEKEPFP SAVTIKSWVD KMQEDLVTLA KTASGVNQLV DIYEKYQDLY TVEPNNARQL VEIAARDIEK LLSNRSKAL VRLALEAEKV QAAHQWREDF ASNEVVYYNA KDDLDPEKND SEPGSQRIKP VFIEDANFGR QISYQHAAVH I PTDIYEGS ...String:
HHHHHHHHWS HPQFEKEPFP SAVTIKSWVD KMQEDLVTLA KTASGVNQLV DIYEKYQDLY TVEPNNARQL VEIAARDIEK LLSNRSKAL VRLALEAEKV QAAHQWREDF ASNEVVYYNA KDDLDPEKND SEPGSQRIKP VFIEDANFGR QISYQHAAVH I PTDIYEGS TIVLNELNWT SALDEVFKKN REEDPSLLWQ VFGSATGLAR YYPASPWVDN SRTPNKIDLY DVRRRPWYIQ GA ASPKDML ILVDVSGSVS GLTLKLIRTS VSEMLETLSD DDFVNVASFN SNAQDVSCFQ HLVQANVRNK KVLKDAVNNI TAK GITDYK KGFSFAFEQL LNYNVSRANC NKIIMLFTDG GEERAQEIFN KYNKDKKVRV FTFSVGQHNY DRGPIQWMAC ENKG YYYEI PSIGAIRINT QEYLDVLGRP MVLAGDKAKQ VQWTNVYLDA LELGLVITGT LPVFNITGQF ENKTNLKNQL ILGVM GVDV SLEDIKRLTP RFTLCPNGYY FAIDPNGYVL LHPNLQPKNP KSQEPVTLDF LDAELENDIK VEIRNKMIDG ESGEKT FRT LVKSQDERYI DKGNRTYTWT PVNGTDYSLA LVLPTYSFYY IKAKLEETIT QARSKKGKMK DSETLKPDNF EESGYTF IA PRDYCNDLKI SDNNTEFLLN FNEFIDRHHH HHHHHKTPNN PSCNADLINR VLLDAGFTNE LVQNYWSKQK NIKGVKAR F VVTDGGITRV YPKEAGENWQ ENPETYEDSF YKRSLDNDNY VFTAPYFNKS GPGAYESGIM VSKAVEIYIQ GKLLKPAVV GIKIDVNSWI ENFTKTSIRD PCAGPVCDCK RNSDVMDCVI LDDGGFLLMA NHDDYTNQIG RFFGEIDPSL MRHLVNISVY AFNKSYDYQ SVCEPGAAPK QGAGHRSAYV PSVADILQIG WWATAAAWSI LQQFLLSLTF PRLLEAVEME DDDFTASLSK Q SCITEQTQ YFFDNDSKSF SGVLDCGNCS RIFHGEKLMN TNLIFIMVES KGTCPCDTRL LIQAEQTSDG PNPCDMVKQP RY RKGPDVC FDNNVLEDYT DCGGVSG

UniProtKB: Voltage-dependent calcium channel subunit alpha-2/delta-1

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: Crisugabalin

MacromoleculeName: Crisugabalin / type: ligand / ID: 5 / Number of copies: 1 / Formula: A1ESQ
Molecular weightTheoretical: 209.285 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI/PHILIPS CM300FEG/HE
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.1 µm

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8if3

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 226483
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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