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- PDB-7wbj: Cryo-EM structure of N-terminal modified human vasoactive intesti... -

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Entry
Database: PDB / ID: 7wbj
TitleCryo-EM structure of N-terminal modified human vasoactive intestinal polypeptide receptor 2 (VIP2R) in complex with PACAP27 and Gs
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody-35Single-domain antibody
  • Pituitary adenylate cyclase-activating polypeptide 27Pituitary adenylate cyclase-activating peptide
  • 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 / vasoactive intestinal polypeptide receptor activity / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of growth hormone secretion / sensory perception of chemical stimulus / mu-type opioid receptor binding / NGF-independant TRKA activation / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / regulation of G protein-coupled receptor signaling pathway ...pituitary adenylate cyclase activating polypeptide activity / vasoactive intestinal polypeptide receptor activity / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of growth hormone secretion / sensory perception of chemical stimulus / mu-type opioid receptor binding / NGF-independant TRKA activation / 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 / Ca2+ pathway / Activation of G protein gated Potassium channels / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (z) signalling events / G protein-coupled peptide receptor activity / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / Adrenaline,noradrenaline inhibits insulin secretion / 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 / Glucagon-type ligand receptors / alkylglycerophosphoethanolamine phosphodiesterase activity / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / insulin secretion / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / beta-2 adrenergic receptor binding / G alpha (q) signalling events / peptide hormone receptor binding / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / cAMP-mediated signaling / negative regulation of cell cycle / photoreceptor outer segment / D1 dopamine receptor binding / neuropeptide signaling pathway / positive regulation of protein kinase activity / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / cardiac muscle cell apoptotic process / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / activation of adenylate cyclase activity / photoreceptor inner segment / adenylate cyclase activator activity / female pregnancy / G protein-coupled receptor activity / negative regulation of smooth muscle cell proliferation / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / positive regulation of GTPase activity / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / sensory perception of taste / neuron projection development / G-protein beta-subunit binding / heterotrimeric G-protein complex / regulation of protein localization / signaling receptor complex adaptor activity / retina development in camera-type eye / cell-cell signaling / GTPase binding / cell body / phospholipase C-activating G protein-coupled receptor signaling pathway
Similarity search - Function
GPCR, family 2, vasoactive intestinal peptide receptor 2 / : / GPCR, family 2, vasoactive intestinal peptide receptor / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain ...GPCR, family 2, vasoactive intestinal peptide receptor 2 / : / GPCR, family 2, vasoactive intestinal peptide receptor / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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. / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
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 speciesHomo sapiens (human)
Bos taurus (cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 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
DepositionDec 16, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Vasoactive intestinal polypeptide receptor 2
L: Pituitary adenylate cyclase-activating polypeptide 27
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
N: Nanobody-35


Theoretical massNumber of molelcules
Total (without water)164,9826
Polymers164,9826
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#3: 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 (cattle) / Gene: GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04896
#4: 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
#5: 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 (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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

#1: 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: 49172.656 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
#2: Protein/peptide Pituitary adenylate cyclase-activating polypeptide 27 / Pituitary adenylate cyclase-activating peptide / PACAP-27 / PACAP27


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


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)

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Details

Sequence detailsThe LgBit has been used for NanoBiT tethering strategy on B chain.

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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
2Vasoactive intestinal polypeptide receptor 2COMPLEX#11RECOMBINANT
3Pituitary adenylate cyclase-activating polypeptide 27Pituitary adenylate cyclase-activating peptideCOMPLEX#21SYNTHETIC
4Guanine nucleotide-binding protein G(s) subunit alpha isoforms short/G(I)/G(S)/G(O) subunit gamma-2COMPLEX#3, #51RECOMBINANT
5Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#41RECOMBINANT
6Nanobody-35Single-domain antibodyCOMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
23Bos taurus (cattle)9913
34Rattus norvegicus (Norway rat)10116
45synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
34Spodoptera frugiperda (fall armyworm)7108
45Escherichia coli (E. coli)562
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 FIELDBright-field microscopy / 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
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.42 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 770771 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049182
ELECTRON MICROSCOPYf_angle_d0.56512448
ELECTRON MICROSCOPYf_dihedral_angle_d4.5611242
ELECTRON MICROSCOPYf_chiral_restr0.0431403
ELECTRON MICROSCOPYf_plane_restr0.0041584

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