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- PDB-7cz5: Cryo-EM structure of the human growth hormone-releasing hormone r... -

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Basic information

Entry
Database: PDB / ID: 7cz5
TitleCryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
  • Nanobody35
  • Somatoliberin
KeywordsMEMBRANE PROTEIN / cognate receptor / Class B G-protein-coupled receptors / single particle
Function / homology
Function and homology information


regulation of intracellular steroid hormone receptor signaling pathway / somatotropin secreting cell development / growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / regulation of protein metabolic process ...regulation of intracellular steroid hormone receptor signaling pathway / somatotropin secreting cell development / growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / regulation of protein metabolic process / positive regulation of multicellular organism growth / multicellular organismal reproductive process / neuropeptide hormone activity / 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 protein-coupled peptide receptor activity / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / hormone metabolic process / nuclear outer membrane / 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 / 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 / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of insulin-like growth factor receptor signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / nuclear inner membrane / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / response to food / 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 / growth factor binding / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / photoreceptor outer segment / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / response to glucocorticoid / cell maturation / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase activator activity / lactation / photoreceptor inner segment / trans-Golgi network membrane / secretory granule / establishment of localization in cell / G protein-coupled receptor activity / determination of adult lifespan / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / bone development / response to insulin / multicellular organism growth / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton
Similarity search - Function
GPCR, family 2, growth hormone-releasing hormone 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. ...GPCR, family 2, growth hormone-releasing hormone 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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
CHOLESTEROL / PALMITIC ACID / Somatoliberin / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Growth hormone-releasing hormone receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (cattle)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsZhou, F. / Zhang, H. / Cong, Z. / Zhao, L. / Zhou, Q. / Mao, C. / Cheng, X. / Shen, D. / Cai, X. / Ma, C. ...Zhou, F. / Zhang, H. / Cong, Z. / Zhao, L. / Zhou, Q. / Mao, C. / Cheng, X. / Shen, D. / Cai, X. / Ma, C. / Wang, Y. / Dai, A. / Zhou, Y. / Sun, W. / Zhao, F. / Zhao, S. / Jiang, H. / Jiang, Y. / Yang, D. / Xu, H.E. / Zhang, Y. / Wang, M.
CitationJournal: Nat Commun / Year: 2020
Title: Structural basis for activation of the growth hormone-releasing hormone receptor.
Authors: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / ...Authors: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / Fenghui Zhao / Suwen Zhao / Hualiang Jiang / Yi Jiang / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang /
Abstract: Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). ...Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 Å. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the α-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.
History
DepositionSep 7, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
R: Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
P: Somatoliberin
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: Nanobody35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,5629
Polymers177,6636
Non-polymers9003
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16410 Å2
ΔGint-79 kcal/mol
Surface area46050 Å2

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Components

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Protein , 2 types, 2 molecules RN

#1: Protein Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor / GHRH receptor / Growth hormone-releasing factor receptor / GRFR


Mass: 61651.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GHRHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02643
#6: Protein Nanobody35


Mass: 13711.284 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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

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


Mass: 45683.434 Da / Num. of mol.: 1
Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092
#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/peptide , 1 types, 1 molecules P

#3: Protein/peptide Somatoliberin / Growth hormone-releasing factor / GRF / Growth hormone-releasing hormone / GHRH / Somatocrinin / Somatorelin


Mass: 5048.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01286

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Non-polymers , 3 types, 6 molecules

#7: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H32O2
#8: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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
IDNameTypeDetailsEntity IDParent-IDSource
1Growth hormone-releasing hormone receptor - Gs protein complexCOMPLEXgrowth hormone-releasing hormone growth hormone-releasing hormone receptor Gs protein Nanobody35#1-#60MULTIPLE SOURCES
2hormone receptor, G(s) subunit alpha isoformsCOMPLEX#1-#21RECOMBINANT
3hormoneCOMPLEX#31RECOMBINANT
4G(s) subunit beta-1COMPLEX#41RECOMBINANT
5G(s) subunit gamma-2COMPLEX#51RECOMBINANT
6Nanobody35COMPLEX#61RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Rattus norvegicus (Norway rat)10116
45Bos taurus (cattle)9913
56synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
34Spodoptera frugiperda (fall armyworm)7108
45Spodoptera frugiperda (fall armyworm)7108
56Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
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
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 307018 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048508
ELECTRON MICROSCOPYf_angle_d0.60511518
ELECTRON MICROSCOPYf_dihedral_angle_d12.495035
ELECTRON MICROSCOPYf_chiral_restr0.0451292
ELECTRON MICROSCOPYf_plane_restr0.0041460

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