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- PDB-7xna: Crystal structure of somatostatin receptor 2 (SSTR2) with peptide... -

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Basic information

Entry
Database: PDB / ID: 7xna
TitleCrystal structure of somatostatin receptor 2 (SSTR2) with peptide antagonist CYN 154806
Components
  • CYN 154806
  • Somatostatin receptor type 2,Endo-1,4-beta-xylanase
KeywordsSIGNALING PROTEIN/INHIBITOR / G protein-coupled receptor / somatostatin receptor 2 / STRUCTURAL PROTEIN / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


somatostatin receptor activity / peristalsis / neuropeptide binding / cellular response to glucocorticoid stimulus / endo-1,4-beta-xylanase activity / endo-1,4-beta-xylanase / response to starvation / xylan catabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway ...somatostatin receptor activity / peristalsis / neuropeptide binding / cellular response to glucocorticoid stimulus / endo-1,4-beta-xylanase activity / endo-1,4-beta-xylanase / response to starvation / xylan catabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / forebrain development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / cerebellum development / cellular response to estradiol stimulus / PDZ domain binding / G alpha (i) signalling events / spermatogenesis / neuron projection / negative regulation of cell population proliferation / plasma membrane / cytosol
Similarity search - Function
Somatostatin receptor 2 / Somatostatin receptor family / Glycoside hydrolase family 11, active site 2 / Glycosyl hydrolases family 11 (GH11) active site signature 2. / Glycoside hydrolase family 11, active site 1 / Glycosyl hydrolases family 11 (GH11) active site signature 1. / Glycoside hydrolase family 11 / Glycosyl hydrolases family 11 (GH11) domain / Glycosyl hydrolases family 11 / Glycosyl hydrolases family 11 (GH11) domain profile. ...Somatostatin receptor 2 / Somatostatin receptor family / Glycoside hydrolase family 11, active site 2 / Glycosyl hydrolases family 11 (GH11) active site signature 2. / Glycoside hydrolase family 11, active site 1 / Glycosyl hydrolases family 11 (GH11) active site signature 1. / Glycoside hydrolase family 11 / Glycosyl hydrolases family 11 (GH11) domain / Glycosyl hydrolases family 11 / Glycosyl hydrolases family 11 (GH11) domain profile. / Glycoside hydrolase family 11/12 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Endo-1,4-beta-xylanase / Somatostatin receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Niallia circulans (bacteria)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsZhao, W. / Han, S. / Qiu, N. / Feng, W. / Lu, M. / Yang, D. / Wang, M.-W. / Wu, B. / Zhao, Q.
Funding support China, 8items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)32161133011 China
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)82121005 China
National Science Foundation (NSF, China)81872915 China
National Science Foundation (NSF, China)82073904 China
National Science Foundation (NSF, China)81773792 China
National Science Foundation (NSF, China)81973373 China
National Science Foundation (NSF, China)21704064 China
CitationJournal: Cell Res / Year: 2022
Title: Structural insights into ligand recognition and selectivity of somatostatin receptors.
Authors: Wenli Zhao / Shuo Han / Na Qiu / Wenbo Feng / Mengjie Lu / Wenru Zhang / Mu Wang / Qingtong Zhou / Shutian Chen / Wei Xu / Juan Du / Xiaojing Chu / Cuiying Yi / Antao Dai / Liaoyuan Hu / ...Authors: Wenli Zhao / Shuo Han / Na Qiu / Wenbo Feng / Mengjie Lu / Wenru Zhang / Mu Wang / Qingtong Zhou / Shutian Chen / Wei Xu / Juan Du / Xiaojing Chu / Cuiying Yi / Antao Dai / Liaoyuan Hu / Michelle Y Shen / Yaping Sun / Qing Zhang / Yingli Ma / Wenge Zhong / Dehua Yang / Ming-Wei Wang / Beili Wu / Qiang Zhao /
Abstract: Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for ...Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.
History
DepositionApr 28, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 17, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Somatostatin receptor type 2,Endo-1,4-beta-xylanase
B: CYN 154806


Theoretical massNumber of molelcules
Total (without water)66,6842
Polymers66,6842
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-10 kcal/mol
Surface area21900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.150, 85.210, 163.690
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Somatostatin receptor type 2,Endo-1,4-beta-xylanase / SS-2-R / SS2-R / SS2R / SRIF-1 / SSTR2 / Xylanase / 1 / 4-beta-D-xylan xylanohydrolase


Mass: 65500.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: fusion protein of SSTR2 and Endo-1,4-beta-xylanase
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Niallia circulans (bacteria)
Gene: SSTR2, xlnA / Production host: Insecta environmental sample (insect)
References: UniProt: P30874, UniProt: P09850, endo-1,4-beta-xylanase
#2: Protein/peptide CYN 154806


Mass: 1183.359 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 7
Details: 100-300 mM ammonium sulphate, 6-10% PEG2000, 1 mg/ml CYN 154806, and 0.1 M HEPES, pH 7.0

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.65→40.82 Å / Num. obs: 17481 / % possible obs: 97.7 % / Redundancy: 3.69 % / Biso Wilson estimate: 58 Å2 / CC1/2: 0.954 / Net I/σ(I): 3.1
Reflection shellResolution: 2.65→2.745 Å / Num. unique obs: 1711 / CC1/2: 0.712

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
PHENIX1.15.2_3472refinement
HKL-2000data reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4N6H, 2B45

4n6h

2b45


Resolution: 2.65→40.82 Å / SU ML: 0.352 / Cross valid method: FREE R-VALUE / σ(F): 100 / Phase error: 29.1143
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2904 --
Rwork0.2196 15713 -
obs-17459 97.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.65→40.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3694 0 84 0 3778
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013891
X-RAY DIFFRACTIONf_angle_d1.20545318
X-RAY DIFFRACTIONf_chiral_restr0.071599
X-RAY DIFFRACTIONf_plane_restr0.0067647
X-RAY DIFFRACTIONf_dihedral_angle_d16.39591298
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.730.3181420.22091280X-RAY DIFFRACTION97.53
2.73-2.820.28681440.22881306X-RAY DIFFRACTION98.51
2.82-2.920.33391410.23561260X-RAY DIFFRACTION97.56
2.92-3.030.32081450.24751313X-RAY DIFFRACTION98.71
3.03-3.170.35471430.25351289X-RAY DIFFRACTION98.15
3.17-3.340.29921460.24431306X-RAY DIFFRACTION98.91
3.34-3.550.29331460.24041315X-RAY DIFFRACTION98.12
3.55-3.820.26821440.21961299X-RAY DIFFRACTION97.43
3.82-4.210.30011460.20511312X-RAY DIFFRACTION97.85
4.21-4.810.27581460.19511308X-RAY DIFFRACTION97.32
4.81-6.060.28281480.22531341X-RAY DIFFRACTION97.07
6.06-40.820.27541560.20741384X-RAY DIFFRACTION95.3

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