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- PDB-8wss: Cryo-EM structure of Melanin-Concentrating Hormone Receptor 1 with MCH -

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Entry
Database: PDB / ID: 8wss
TitleCryo-EM structure of Melanin-Concentrating Hormone Receptor 1 with MCH
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Melanin-concentrating hormone receptor 1
  • Pro-MCH
  • Scfv16
KeywordsMEMBRANE PROTEIN / Melanin-Concentrating Hormone Receptors1 / GPCR
Function / homology
Function and homology information


melanin-concentrating hormone activity / type 1 melanin-concentrating hormone receptor binding / melanin-concentrating hormone receptor activity / negative regulation of synaptic transmission, dopaminergic / neuropeptide receptor activity / BBSome-mediated cargo-targeting to cilium / positive regulation of calcium ion transport / neuropeptide binding / feeding behavior / non-motile cilium ...melanin-concentrating hormone activity / type 1 melanin-concentrating hormone receptor binding / melanin-concentrating hormone receptor activity / negative regulation of synaptic transmission, dopaminergic / neuropeptide receptor activity / BBSome-mediated cargo-targeting to cilium / positive regulation of calcium ion transport / neuropeptide binding / feeding behavior / non-motile cilium / ciliary membrane / hormone binding / neuropeptide signaling pathway / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / generation of precursor metabolites and energy / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor activity / G protein-coupled receptor binding / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / positive regulation of cytosolic calcium ion concentration / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / spermatogenesis / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / cell differentiation / neuron projection / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / cell population proliferation / cilium / ciliary basal body / G protein-coupled receptor signaling pathway
Similarity search - Function
Pre-pro melanin-concentrating hormone / Pro-melanin-concentrating hormone (Pro-MCH) / Melanin-concentrating hormone receptor 1 / Melanin-concentrating hormone receptor / G-protein alpha subunit, group I / 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 ...Pre-pro melanin-concentrating hormone / Pro-melanin-concentrating hormone (Pro-MCH) / Melanin-concentrating hormone receptor 1 / Melanin-concentrating hormone receptor / G-protein alpha subunit, group I / 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 / 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-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Pro-MCH / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Melanin-concentrating hormone receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsZhao, L. / He, Q. / Yuan, Q. / Gu, Y. / Shan, H. / Hu, W. / Wu, K. / Xu, H.E. / Zhang, Y. / Wu, C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Discov / Year: 2024
Title: Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.
Authors: Qian He / Qingning Yuan / Hong Shan / Canrong Wu / Yimin Gu / Kai Wu / Wen Hu / Yumu Zhang / Xinheng He / H Eric Xu / Li-Hua Zhao /
Abstract: Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are ...Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, G, and MCHR2 can only couple to G. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G and MCH-activated MCHR2 with G at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.
History
DepositionOct 17, 2023Deposition site: PDBJ / Processing site: PDBJ
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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(i) subunit alpha-1
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
H: Scfv16
L: Pro-MCH
R: Melanin-concentrating hormone receptor 1


Theoretical massNumber of molelcules
Total (without water)165,8036
Polymers165,8036
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 41055.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#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.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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

#4: Antibody Scfv16


Mass: 30363.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein/peptide Pro-MCH


Mass: 2391.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PMCH / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P20382
#6: Protein Melanin-concentrating hormone receptor 1 / MCH receptor 1 / MCH-R1 / MCHR-1 / G-protein coupled receptor 24 / MCH-1R / MCH1R / MCHR / SLC-1 / ...MCH receptor 1 / MCH-R1 / MCHR-1 / G-protein coupled receptor 24 / MCH-1R / MCH1R / MCHR / SLC-1 / Somatostatin receptor-like protein


Mass: 43716.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCHR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q99705

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Details

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: Mechanisms of Ligand Recognition and Activation of Melanin-Concentrating Hormone Receptors1
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.16 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.04
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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 311033 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049247
ELECTRON MICROSCOPYf_angle_d0.69812595
ELECTRON MICROSCOPYf_dihedral_angle_d4.6051304
ELECTRON MICROSCOPYf_chiral_restr0.0421471
ELECTRON MICROSCOPYf_plane_restr0.0061536

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