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- PDB-8ucn: Komagataella pastoris Cytochrome c oxidase in complex with human ... -

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Basic information

Entry
Database: PDB / ID: 8ucn
TitleKomagataella pastoris Cytochrome c oxidase in complex with human VMAT2 and Histamine
Components
  • (Cytochrome c oxidase subunit ...) x 9
  • Synaptic vesicular amine transporter
KeywordsMEMBRANE PROTEIN / VMAT / SLC18 / vascular monoamine transporter / Cytochrome c oxidase-VMAT2 complex / Neurotransmitters / Histamine
Function / homology
Function and homology information


serotonin secretion by mast cell / somato-dendritic dopamine secretion / histamine uptake / aminergic neurotransmitter loading into synaptic vesicle / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / clathrin-sculpted monoamine transport vesicle membrane / Serotonin Neurotransmitter Release Cycle / serotonin:sodium:chloride symporter activity / Norepinephrine Neurotransmitter Release Cycle ...serotonin secretion by mast cell / somato-dendritic dopamine secretion / histamine uptake / aminergic neurotransmitter loading into synaptic vesicle / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / clathrin-sculpted monoamine transport vesicle membrane / Serotonin Neurotransmitter Release Cycle / serotonin:sodium:chloride symporter activity / Norepinephrine Neurotransmitter Release Cycle / Dopamine Neurotransmitter Release Cycle / serotonin uptake / : / histamine secretion by mast cell / dopaminergic synapse / monoamine transmembrane transporter activity / respiratory chain complex IV / : / cytochrome-c oxidase / mitochondrial electron transport, cytochrome c to oxygen / SLC-mediated transport of neurotransmitters / cytochrome-c oxidase activity / neurotransmitter transport / electron transport coupled proton transport / negative regulation of reactive oxygen species biosynthetic process / secretory granule membrane / response to amphetamine / post-embryonic development / locomotory behavior / response to toxic substance / terminal bouton / synaptic vesicle / synaptic vesicle membrane / chemical synaptic transmission / oxidoreductase activity / mitochondrial inner membrane / axon / heme binding / centrosome / dendrite / membrane / metal ion binding / plasma membrane
Similarity search - Function
Cytochrome c oxidase, subunit VIIa, fungal / : / Cytochrome c oxidase subunit VIIc / Cytochrome c oxidase subunit IV family / Cytochrome c oxidase subunit VIIc superfamily / Cytochrome c oxidase subunit IV superfamily / Cytochrome c oxidase subunit VIIc / Cytochrome c oxidase subunit IV / Cytochrome c oxidase, subunit Va/VI / Cytochrome c oxidase, subunit Va/VI superfamily ...Cytochrome c oxidase, subunit VIIa, fungal / : / Cytochrome c oxidase subunit VIIc / Cytochrome c oxidase subunit IV family / Cytochrome c oxidase subunit VIIc superfamily / Cytochrome c oxidase subunit IV superfamily / Cytochrome c oxidase subunit VIIc / Cytochrome c oxidase subunit IV / Cytochrome c oxidase, subunit Va/VI / Cytochrome c oxidase, subunit Va/VI superfamily / Cytochrome c oxidase subunit Va / Cytochrome c oxidase subunit VII / Cytochrome c oxidase subunit VII / Cytochrome c oxidase, subunit Vb / Cytochrome c oxidase subunit Vb / Cytochrome c oxidase subunit Vb, zinc binding domain profile. / Cytochrome c oxidase, subunit Vb superfamily / Cytochrome c oxidase subunit III domain / Cytochrome c oxidase subunit I domain / Cytochrome c oxidase subunit III / Cytochrome c oxidase subunit III-like / Cytochrome c oxidase, subunit III, 4-helical bundle / Cytochrome c oxidase subunit III / Heme-copper oxidase subunit III family profile. / Cytochrome c oxidase subunit III-like superfamily / Cytochrome c oxidase, subunit I, copper-binding site / Heme-copper oxidase catalytic subunit, copper B binding region signature. / Cytochrome c oxidase-like, subunit I domain / Cytochrome oxidase subunit I profile. / Cytochrome c oxidase subunit I / Cytochrome c oxidase-like, subunit I superfamily / Cytochrome C and Quinol oxidase polypeptide I / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
COPPER (II) ION / DINUCLEAR COPPER ION / HEME-A / HISTAMINE / PHOSPHATIDYLETHANOLAMINE / Cytochrome c oxidase subunit 9, mitochondrial / Cytochrome c oxidase subunit 8, mitochondrial / Cytochrome c oxidase subunit 7 / Cytochrome c oxidase subunit 4, mitochondrial / Cytochrome c oxidase subunit 6, mitochondrial ...COPPER (II) ION / DINUCLEAR COPPER ION / HEME-A / HISTAMINE / PHOSPHATIDYLETHANOLAMINE / Cytochrome c oxidase subunit 9, mitochondrial / Cytochrome c oxidase subunit 8, mitochondrial / Cytochrome c oxidase subunit 7 / Cytochrome c oxidase subunit 4, mitochondrial / Cytochrome c oxidase subunit 6, mitochondrial / Cytochrome c oxidase subunit 5B / Cytochrome c oxidase subunit 3 / Cytochrome c oxidase subunit 1 / Synaptic vesicular amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Komagataella pastoris (fungus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsYe, J. / Liu, B. / Li, W.
Funding support United States, 1items
OrganizationGrant numberCountry
American Heart AssociationEstablished Investigator Award United States
CitationJournal: Cell Rep / Year: 2025
Title: Molecular basis of vesicular monoamine transport and neurological drug interactions.
Authors: Jin Ye / Huaping Chen / Aaron Ammerman / Yi Wang / Kaituo Wang / Jinbin Xu / Bin Liu / Weikai Li /
Abstract: Vesicular monoamine transporter 2 (VMAT2) stores monoamine neurotransmitters in synaptic vesicles to regulate their release. VMAT2 is a primary target in neurological disorder treatment and ...Vesicular monoamine transporter 2 (VMAT2) stores monoamine neurotransmitters in synaptic vesicles to regulate their release. VMAT2 is a primary target in neurological disorder treatment and contributes to amphetamine-induced psychostimulation. Here, we report cryo-electron microscopy structures of human VMAT2 capturing a cytoplasmic-open state with reserpine and lumenal-facing states with serotonin and histamine in open, amphetamine in less open, tetrabenazine in fully occluded, and unbound VMAT2 in partially occluded conformations. This structural flexibility facilitates tetrabenazine binding and proton-driven monoamine accumulation. VMAT2 binds serotonin and histamine in opposite orientations through two negatively charged sites, one functioning in protonation. Amphetamine binds in the same pocket without engaging this protonation site. Liposome-based analyses demonstrate that amphetamine directly induces the release of a fluorescent monoamine analog via VMAT2, consistent with an exchange mechanism underlying psychostimulation. These findings reveal the molecular basis of monoamine storage and drug interactions by VMAT2, informing therapeutic development for neurological diseases and substance abuse.
History
DepositionSep 26, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.0Oct 9, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 9, 2024Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 9, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Oct 9, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 9, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Apr 22, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Synaptic vesicular amine transporter
a: Cytochrome c oxidase subunit 1
b: Cytochrome c oxidase subunit 2
c: Cytochrome c oxidase subunit 3
d: Cytochrome c oxidase subunit 4
e: Cytochrome c oxidase subunit 5
f: Cytochrome c oxidase subunit 6
g: Cytochrome c oxidase subunit 7
h: Cytochrome c oxidase subunit 8
i: Cytochrome c oxidase subunit 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)234,92520
Polymers229,91610
Non-polymers5,00910
Water00
1


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

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Synaptic vesicular amine transporter


Mass: 55749.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC18A2 / Production host: Komagataella pastoris (fungus) / References: UniProt: Q05940

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Cytochrome c oxidase subunit ... , 9 types, 9 molecules abcdefghi

#2: Protein Cytochrome c oxidase subunit 1


Mass: 58857.352 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2R0K8
#3: Protein Cytochrome c oxidase subunit 2


Mass: 26886.889 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus)
#4: Protein Cytochrome c oxidase subunit 3


Mass: 30561.145 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2R0J6
#5: Protein Cytochrome c oxidase subunit 4


Mass: 12970.557 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2QT92
#6: Protein Cytochrome c oxidase subunit 5


Mass: 14519.340 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2QVW8
#7: Protein Cytochrome c oxidase subunit 6


Mass: 11851.136 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2QVA2
#8: Protein Cytochrome c oxidase subunit 7


Mass: 6573.613 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2QS38
#9: Protein/peptide Cytochrome c oxidase subunit 8


Mass: 5456.455 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: F2QRE4
#10: Protein Cytochrome c oxidase subunit 9


Mass: 6490.561 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Komagataella pastoris (fungus) / References: UniProt: A0A1G4KPQ9

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Non-polymers , 6 types, 10 molecules

#11: Chemical ChemComp-HSM / HISTAMINE


Mass: 111.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9N3 / Feature type: SUBJECT OF INVESTIGATION / Comment: neurotransmitter, hormone*YM
#12: Chemical ChemComp-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical ChemComp-HEA / HEME-A


Mass: 852.837 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C49H56FeN4O6 / Feature type: SUBJECT OF INVESTIGATION
#14: Chemical ChemComp-CUA / DINUCLEAR COPPER ION


Mass: 127.092 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cu2 / Feature type: SUBJECT OF INVESTIGATION
#15: Chemical
ChemComp-PTY / PHOSPHATIDYLETHANOLAMINE


Mass: 734.039 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C40H80NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#16: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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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: Komagataella pastoris Cytochrome c oxidase in complex with human VMAT2 and Histamine
Type: COMPLEX / Entity ID: #1-#10 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.225 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Komagataella pastoris (fungus)4922
Source (recombinant)Organism: Komagataella pastoris (fungus)
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Cytochrome c oxidase-VMAT2-Histamine PARTICLE
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 77 K / Temperature (min): 63 K
Image recordingAverage exposure time: 3 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.18.2_3874:model refinement
3EPUimage acquisition
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84534 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00615563
ELECTRON MICROSCOPYf_angle_d0.88721177
ELECTRON MICROSCOPYf_dihedral_angle_d17.1122249
ELECTRON MICROSCOPYf_chiral_restr0.0572380
ELECTRON MICROSCOPYf_plane_restr0.0082586

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