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- PDB-7xn9: Crystal structure of SSTR2 and L-054,522 complex -

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Basic information

Entry
Database: PDB / ID: 7xn9
TitleCrystal structure of SSTR2 and L-054,522 complex
ComponentsSomatostatin receptor type 2,Endo-1,4-beta-xylanase
KeywordsSIGNARING PROTEIN/INHIBITOR / G protein-coupled receptor / somatostatin receptor 2 / STRUCTURAL PROTEIN / SIGNALING PROTEIN / SIGNARING 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 / cerebellum development / Peptide ligand-binding receptors / 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
Chem-GI9 / Endo-1,4-beta-xylanase / Somatostatin receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Niallia circulans (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,9423
Polymers66,0581
Non-polymers8842
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area540 Å2
ΔGint7 kcal/mol
Surface area22120 Å2
Unit cell
Length a, b, c (Å)74.520, 97.957, 170.499
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,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 / Xylanase / 1 / 4-beta-D-xylan xylanohydrolase


Mass: 66058.125 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: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#3: Chemical ChemComp-GI9 / tert-butyl (2S)-6-azanyl-2-[[(2R,3S)-3-(1H-indol-3-yl)-2-[[4-(2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]carbonylamino]butanoyl]amino]hexanoate / L-054,52


Mass: 645.792 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H47N7O5 / Feature type: SUBJECT OF INVESTIGATION
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: 2.36 Å3/Da / Density % sol: 47.77 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 7
Details: 100-400 mM lithium nitrate, 6-10% PEG2000, 100 mM L-054,522, 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 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→37.26 Å / Num. obs: 19455 / % possible obs: 99.2 % / Redundancy: 7.5 % / Biso Wilson estimate: 64 Å2 / CC1/2: 0.996 / Net I/σ(I): 10.91
Reflection shellResolution: 2.6→2.693 Å / Num. unique obs: 1875 / CC1/2: 0.755

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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

4n6h


Resolution: 2.6→37.26 Å / SU ML: 0.3506 / Cross valid method: NONE / σ(F): 1.37 / Phase error: 26.2249
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2647 987 5.07 %
Rwork0.2126 18462 -
obs0.2153 19449 99.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 64.25 Å2
Refinement stepCycle: LAST / Resolution: 2.6→37.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3725 0 62 0 3787
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01293899
X-RAY DIFFRACTIONf_angle_d1.10775330
X-RAY DIFFRACTIONf_chiral_restr0.0623598
X-RAY DIFFRACTIONf_plane_restr0.0059643
X-RAY DIFFRACTIONf_dihedral_angle_d15.76191318
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.740.31091570.25132518X-RAY DIFFRACTION97.27
2.74-2.910.30621490.23532606X-RAY DIFFRACTION99.17
2.91-3.130.31191460.21832608X-RAY DIFFRACTION99.71
3.13-3.450.31241290.22482641X-RAY DIFFRACTION99.89
3.45-3.950.26341390.21652642X-RAY DIFFRACTION99.82
3.95-4.970.25471310.20782675X-RAY DIFFRACTION99.75
4.97-37.260.23431360.19992772X-RAY DIFFRACTION99.05
Refinement TLS params.Method: refined / Origin x: 10.2653442 Å / Origin y: 35.3038965762 Å / Origin z: 25.1864363393 Å
111213212223313233
T0.402664134967 Å20.0118256096329 Å20.00183707199482 Å2-0.431862106659 Å20.0241529093601 Å2--0.410214393369 Å2
L0.233032827763 °20.31432794334 °2-0.0315366460532 °2-1.41073602715 °20.50168810066 °2--0.0624327924596 °2
S-0.0690033691037 Å °-0.0300638912847 Å °0.0214469442884 Å °-0.268610119641 Å °0.00741832138349 Å °0.107656804168 Å °-0.0539248951568 Å °-0.027865071983 Å °0.0633178588147 Å °
Refinement TLS groupSelection details: all

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