7CZ5

Cryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.60 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report



Literature

Structural basis for activation of the growth hormone-releasing hormone receptor.

Zhou, F.Zhang, H.Cong, Z.Zhao, L.H.Zhou, Q.Mao, C.Cheng, X.Shen, D.D.Cai, X.Ma, C.Wang, Y.Dai, A.Zhou, Y.Sun, W.Zhao, F.Zhao, S.Jiang, H.Jiang, Y.Yang, D.Eric Xu, H.Zhang, Y.Wang, M.W.

(2020) Nat Commun 11: 5205-5205

  • DOI: 10.1038/s41467-020-18945-0
  • Primary Citation of Related Structures:  
    7CZ5

  • PubMed 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). Malfunction in GHRHR signaling is associated with abn ...

    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.


    Organizational Affiliation

    School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China. mwwang@simm.ac.cn.



Macromolecules
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Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptorR556Homo sapiensMutation(s): 0 
Gene Names: GHRHR
Find proteins for Q02643 (Homo sapiens)
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PHAROS  Q02643
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  • Reference Sequence
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Entity ID: 2
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortA394Homo sapiensMutation(s): 8 
Gene Names: GNASGNAS1GSP
Find proteins for P63092 (Homo sapiens)
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PHAROS  P63092
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Entity ID: 3
MoleculeChainsSequence LengthOrganismDetailsImage
SomatoliberinP44Homo sapiensMutation(s): 0 
Gene Names: GHRHGHRF
Find proteins for P01286 (Homo sapiens)
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PHAROS  P01286
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Entity ID: 4
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1B400Rattus norvegicusMutation(s): 0 
Gene Names: Gnb1
Find proteins for P54311 (Rattus norvegicus)
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Entity ID: 5
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2G71Bos taurusMutation(s): 0 
Gene Names: GNG2
Find proteins for P63212 (Bos taurus)
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Entity ID: 6
MoleculeChainsSequence LengthOrganismDetailsImage
Nanobody35N126synthetic constructMutation(s): 0 
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
CLR
Query on CLR

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R
CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
 Ligand Interaction
PLM
Query on PLM

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A, R
PALMITIC ACID
C16 H32 O2
IPCSVZSSVZVIGE-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.60 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2020-11-18
    Type: Initial release