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Entry
Database: PDB / ID: 7vqx
TitleCryo-EM structure of human vasoactive intestinal polypeptide receptor 2 (VIP2R) in complex with PACAP27 and Gs
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody-35
  • Pituitary adenylate cyclase-activating polypeptide 27
  • Vasoactive intestinal polypeptide receptor 2
KeywordsSTRUCTURAL PROTEIN / vasoactive intestinal polypeptide receptor 2 / G protein-coupled receptor / ligand recognition
Function / homology
Function and homology information


pituitary adenylate cyclase activating polypeptide activity / type 1 vasoactive intestinal polypeptide receptor binding / type 2 vasoactive intestinal polypeptide receptor binding / pituitary adenylate cyclase-activating polypeptide receptor activity / vasoactive intestinal polypeptide receptor activity / positive regulation of growth hormone secretion / positive regulation of chemokine (C-C motif) ligand 5 production / sensory perception of chemical stimulus / NGF-independant TRKA activation / mu-type opioid receptor binding ...pituitary adenylate cyclase activating polypeptide activity / type 1 vasoactive intestinal polypeptide receptor binding / type 2 vasoactive intestinal polypeptide receptor binding / pituitary adenylate cyclase-activating polypeptide receptor activity / vasoactive intestinal polypeptide receptor activity / positive regulation of growth hormone secretion / positive regulation of chemokine (C-C motif) ligand 5 production / sensory perception of chemical stimulus / NGF-independant TRKA activation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / regulation of G protein-coupled receptor signaling pathway / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G protein-coupled peptide receptor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / beta-2 adrenergic receptor binding / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / insulin secretion / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / photoreceptor outer segment membrane / G alpha (s) signalling events / G alpha (q) signalling events / spectrin binding / peptide hormone receptor binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / alkylglycerophosphoethanolamine phosphodiesterase activity / negative regulation of cell cycle / positive regulation of protein kinase activity / peptide hormone binding / positive regulation of GTPase activity / photoreceptor outer segment / neuropeptide signaling pathway / D1 dopamine receptor binding / activation of adenylate cyclase activity / adenylate cyclase-activating adrenergic receptor signaling pathway / insulin-like growth factor receptor binding / cardiac muscle cell apoptotic process / photoreceptor inner segment / ionotropic glutamate receptor binding / adenylate cyclase activator activity / female pregnancy / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuron projection development / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / cell-cell signaling / sensory perception of taste / signaling receptor complex adaptor activity / regulation of protein localization / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / cell body
Similarity search - Function
GPCR, family 2, vasoactive intestinal peptide receptor 2 / : / GPCR, family 2, vasoactive intestinal peptide receptor / : / GPCR, family 2, extracellular hormone receptor domain / Hormone receptor fold / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones ...GPCR, family 2, vasoactive intestinal peptide receptor 2 / : / GPCR, family 2, vasoactive intestinal peptide receptor / : / GPCR, family 2, extracellular hormone receptor domain / Hormone receptor fold / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / Few Secondary Structures / Irregular / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Pituitary adenylate cyclase-activating polypeptide / Vasoactive intestinal polypeptide receptor 2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsXu, Y.N. / Feng, W.B. / Zhou, Q.T. / Liang, A.Y. / Li, J. / Dai, A.T. / Zhao, F.H. / Yan, J.H. / Chen, C.W. / Li, H. ...Xu, Y.N. / Feng, W.B. / Zhou, Q.T. / Liang, A.Y. / Li, J. / Dai, A.T. / Zhao, F.H. / Yan, J.H. / Chen, C.W. / Li, H. / Zhao, L.H. / Xia, T. / Jiang, Y. / Xu, H.E. / Yang, D.H. / Wang, M.W.
Funding support China, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)81773792 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
CitationJournal: Nat Commun / Year: 2022
Title: A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2.
Authors: Yingna Xu / Wenbo Feng / Qingtong Zhou / Anyi Liang / Jie Li / Antao Dai / Fenghui Zhao / Jiahui Yan / Chuan-Wei Chen / Hao Li / Li-Hua Zhao / Tian Xia / Yi Jiang / H Eric Xu / Dehua Yang / Ming-Wei Wang /
Abstract: Class B1 of G protein-coupled receptors (GPCRs) comprises 15 members activated by physiologically important peptide hormones. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is ...Class B1 of G protein-coupled receptors (GPCRs) comprises 15 members activated by physiologically important peptide hormones. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, including pulmonary arterial hypertension, autoimmune and psychiatric disorders, in which it is thus a valuable drug target. Here, we report the cryo-electron microscopy structure of the human VIP2R bound to its endogenous ligand PACAP27 and the stimulatory G protein. Different from all reported peptide-bound class B1 GPCR structures, the N-terminal α-helix of VIP2R adopts a unique conformation that deeply inserts into a cleft between PACAP27 and the extracellular loop 1, thereby stabilizing the peptide-receptor interface. Its truncation or extension significantly decreased VIP2R-mediated cAMP accumulation. Our results provide additional information on peptide recognition and receptor activation among class B1 GPCRs and may facilitate the design of better therapeutics.
History
DepositionOct 21, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.0May 18, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 18, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 18, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0May 18, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 18, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jun 25, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 25, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
L: Pituitary adenylate cyclase-activating polypeptide 27
N: Nanobody-35
R: Vasoactive intestinal polypeptide receptor 2


Theoretical massNumber of molelcules
Total (without water)180,3886
Polymers180,3886
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45743.441 Da / Num. of mol.: 1
Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T, A366S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04896
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 43706.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Protein/peptide / Antibody / Protein , 3 types, 3 molecules LNR

#4: Protein/peptide Pituitary adenylate cyclase-activating polypeptide 27 / PACAP-27 / PACAP27


Mass: 3154.642 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P18509
#5: Antibody Nanobody-35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#6: Protein Vasoactive intestinal polypeptide receptor 2 / VIP-R-2 / Helodermin-preferring VIP receptor / Pituitary adenylate cyclase-activating polypeptide ...VIP-R-2 / Helodermin-preferring VIP receptor / Pituitary adenylate cyclase-activating polypeptide type III receptor / PACAP type III receptor / PACAP-R-3 / PACAP-R3 / VPAC2


Mass: 64579.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VIPR2, VIP2R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41587

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Details

Has protein modificationY
Sequence detailsThe LgBit has been used for NanoBiT tethering strategy on B and R chains.

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of the human vasoactive intestinal polypeptide receptor 2 in commplex with PACAP27 and G proteinCOMPLEXall0MULTIPLE SOURCES
2human vasoactive intestinal polypeptide receptor 2COMPLEX#11RECOMBINANT
3Pituitary adenylate cyclase activating peptide-27COMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortCOMPLEX#31RECOMBINANT
5Guanine nucleotide-binding protein G(I) /G(S) /G(T) subunit beta-1COMPLEX#41SYNTHETIC
6Guanine nucleotide-binding protein G(I) /G(S) /G(O) subunit gamma-2COMPLEX#51RECOMBINANT
7Nanobody-35COMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Bos taurus (domestic cattle)9913
32Homo sapiens (human)9606
43Bos taurus (domestic cattle)9913
55synthetic construct (others)32630
66Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
43Spodoptera frugiperda (fall armyworm)7108
55Escherichia coli (E. coli)562
66Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.74 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 602466 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049239
ELECTRON MICROSCOPYf_angle_d0.53912516
ELECTRON MICROSCOPYf_dihedral_angle_d4.4141247
ELECTRON MICROSCOPYf_chiral_restr0.0421404
ELECTRON MICROSCOPYf_plane_restr0.0041594

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