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- PDB-9v2n: Macimorelin bound growth hormone secretagogue receptor in complex... -

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Basic information

Entry
Database: PDB / ID: 9v2n
TitleMacimorelin bound growth hormone secretagogue receptor in complex with Gq
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Engineered G-alpha-q subunit
  • NB35
  • Soluble cytochrome b562,Growth hormone secretagogue receptor type 1,growth hormone secretagogue receptor
  • scFv16
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Macimorelin / growth hormone secretagogue receptor / GHSR / GPCR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


growth hormone secretagogue receptor activity / regulation of hindgut contraction / negative regulation of locomotion involved in locomotory behavior / regulation of growth hormone secretion / positive regulation of small intestinal transit / regulation of gastric motility / growth hormone-releasing hormone receptor activity / response to follicle-stimulating hormone / regulation of transmission of nerve impulse / ghrelin secretion ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / negative regulation of locomotion involved in locomotory behavior / regulation of growth hormone secretion / positive regulation of small intestinal transit / regulation of gastric motility / growth hormone-releasing hormone receptor activity / response to follicle-stimulating hormone / regulation of transmission of nerve impulse / ghrelin secretion / growth hormone secretion / negative regulation of norepinephrine secretion / negative regulation of macrophage apoptotic process / positive regulation of small intestine smooth muscle contraction / positive regulation of appetite / adult feeding behavior / positive regulation of eating behavior / positive regulation of multicellular organism growth / negative regulation of appetite / actin polymerization or depolymerization / cellular response to thyroid hormone stimulus / response to growth hormone / positive regulation of vascular endothelial cell proliferation / response to L-glutamate / regulation of postsynapse organization / negative regulation of interleukin-1 beta production / cellular response to insulin-like growth factor stimulus / positive regulation of fatty acid metabolic process / response to dexamethasone / negative regulation of interleukin-6 production / positive regulation of sprouting angiogenesis / decidualization / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / peptide hormone binding / negative regulation of tumor necrosis factor production / postsynaptic modulation of chemical synaptic transmission / hormone-mediated signaling pathway / response to hormone / Peptide ligand-binding receptors / electron transport chain / synaptic membrane / negative regulation of inflammatory response / Schaffer collateral - CA1 synapse / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / response to estradiol / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to lipopolysaccharide / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / spermatogenesis / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / learning or memory / electron transfer activity / periplasmic space / postsynapse / Extra-nuclear estrogen signaling / neuron projection / iron ion binding / membrane raft / G protein-coupled receptor signaling pathway
Similarity search - Function
Growth hormone secretagogue receptor/motilin receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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 ...Growth hormone secretagogue receptor/motilin receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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 receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
Similarity search - Domain/homology
: / Soluble cytochrome b562 / 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 / Growth hormone secretagogue receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Escherichia coli (E. coli)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.63 Å
AuthorsWang, R. / Sun, J. / Liu, H. / Guo, S. / Zhang, Y. / Hu, W. / Wang, J. / Liu, H. / Zhuang, Y. / Jiang, Y. ...Wang, R. / Sun, J. / Liu, H. / Guo, S. / Zhang, Y. / Hu, W. / Wang, J. / Liu, H. / Zhuang, Y. / Jiang, Y. / Xie, X. / Xu, H. / Wang, Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171187 China
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Acta Pharmacol Sin / Year: 2025
Title: Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor.
Authors: Ruo-Lan Wang / Jun Sun / Heng Liu / Shi-Meng Guo / Yu Zhang / Wen Hu / Jiang Wang / Hong Liu / You-Wen Zhuang / Yi Jiang / Xin Xie / H Eric Xu / Yue Wang /
Abstract: The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition ...The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition is essential for developing therapeutic interventions. In this study, we investigated the molecular recognition mechanisms of two clinically approved drugs: Macimorelin (used for diagnosing adult growth hormone deficiency) and Anamorelin (approved in Japan for cancer cachexia). Using high-resolution cryo-electron microscopy, we determined the structures of GHSR bound to Macimorelin and Anamorelin in complex with G proteins at resolutions of 2.63 Å and 2.52 Å, respectively. We revealed that both drugs occupied a bifurcated binding pocket divided by a conserved salt bridge between E124 and R283. Through systematic mutagenesis and functional studies, we identified the key residues underlying the higher binding affinity of Anamorelin compared to Macimorelin. In addition, structural comparison of GHSR in complex with different G protein subtypes elucidated the mechanisms driving G protein selectivity. Our results provide crucial insights into GHSR-drug interactions and offer valuable guidance for designing more selective and potent GHSR agonists.
History
DepositionMay 20, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 5, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Engineered G-alpha-q subunit
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: NB35
R: Soluble cytochrome b562,Growth hormone secretagogue receptor type 1,growth hormone secretagogue receptor
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)214,4727
Polymers213,9986
Non-polymers4751
Water00
1


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

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Components

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Protein , 2 types, 2 molecules AR

#1: Protein Engineered G-alpha-q subunit


Mass: 41855.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Soluble cytochrome b562,Growth hormone secretagogue receptor type 1,growth hormone secretagogue receptor / Cytochrome b-562 / GHS-R / GH-releasing peptide receptor / GHRP / Ghrelin receptor


Mass: 76149.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, GHSR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: Q92847

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 40226.992 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 , 2 types, 2 molecules NS

#4: Antibody NB35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia phage EcSzw-2 (virus)
#6: Antibody scFv16


Mass: 32561.281 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)

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Non-polymers , 1 types, 1 molecules

#7: Chemical ChemComp-A1EQV / Macimorelin / 2-azanyl-N-[(2R)-1-[[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]amino]-3-(1H-indol-3-yl)-1-oxidanylidene-propan-2-yl]-2-methyl-propanamide


Mass: 474.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O3 / 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: Macimorelin bound growth hormone secretagogue receptor in complex with Gq
Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.3
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.63 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 146801 / Symmetry type: POINT
RefinementHighest resolution: 2.63 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01310118
ELECTRON MICROSCOPYf_angle_d1.10713716
ELECTRON MICROSCOPYf_dihedral_angle_d7.0621378
ELECTRON MICROSCOPYf_chiral_restr0.0411547
ELECTRON MICROSCOPYf_plane_restr0.0041739

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