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- PDB-4zgm: Crystal structure of Semaglutide peptide backbone in complex with... -

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Basic information

Entry
Database: PDB / ID: 4zgm
TitleCrystal structure of Semaglutide peptide backbone in complex with the GLP-1 receptor extracellular domain
Components
  • Glucagon-like peptide 1 receptorGlucagon-like peptide-1 receptor
  • Semaglutide peptide backbone; 8Aib,34R-GLP-1(7-37)-OH
KeywordsSIGNALING PROTEIN / GLP-1 / receptor / complex
Function / homology
Function and homology information


glucagon receptor binding / glucagon-like peptide 1 receptor activity / : / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / post-translational protein targeting to membrane, translocation / feeding behavior / regulation of heart contraction ...glucagon receptor binding / glucagon-like peptide 1 receptor activity / : / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / post-translational protein targeting to membrane, translocation / feeding behavior / regulation of heart contraction / response to psychosocial stress / positive regulation of calcium ion import / cellular response to glucagon stimulus / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / regulation of insulin secretion / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of gluconeogenesis / cAMP-mediated signaling / protein kinase A signaling / activation of adenylate cyclase activity / negative regulation of blood pressure / response to activity / positive regulation of peptidyl-threonine phosphorylation / gluconeogenesis / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / transmembrane signaling receptor activity / positive regulation of peptidyl-serine phosphorylation / glucose homeostasis / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / G alpha (q) signalling events / secretory granule lumen / learning or memory / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / negative regulation of apoptotic process / extracellular space / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
GPCR, family 2, extracellular hormone receptor domain / Glucagon / Hormone receptor fold / : / GPCR, family 2, glucagon-like peptide-1 receptor / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor ...GPCR, family 2, extracellular hormone receptor domain / Glucagon / Hormone receptor fold / : / GPCR, family 2, glucagon-like peptide-1 receptor / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / 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. / Few Secondary Structures / Irregular
Similarity search - Domain/homology
3,6,9,12,15,18-hexaoxahexacosan-1-ol / Pro-glucagon / Glucagon-like peptide 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsReedtz-Runge, S.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
Authors: Lau, J. / Bloch, P. / Schaffer, L. / Pettersson, I. / Spetzler, J. / Kofoed, J. / Madsen, K. / Knudsen, L.B. / McGuire, J. / Steensgaard, D.B. / Strauss, H.M. / Gram, D.X. / Knudsen, S.M. / ...Authors: Lau, J. / Bloch, P. / Schaffer, L. / Pettersson, I. / Spetzler, J. / Kofoed, J. / Madsen, K. / Knudsen, L.B. / McGuire, J. / Steensgaard, D.B. / Strauss, H.M. / Gram, D.X. / Knudsen, S.M. / Nielsen, F.S. / Thygesen, P. / Reedtz-Runge, S. / Kruse, T.
History
DepositionApr 23, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2015Group: Database references
Revision 1.2Oct 7, 2015Group: Database references
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glucagon-like peptide 1 receptor
B: Semaglutide peptide backbone; 8Aib,34R-GLP-1(7-37)-OH
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5174
Polymers17,7282
Non-polymers7892
Water1,58588
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-10 kcal/mol
Surface area8850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.610, 35.790, 42.680
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Glucagon-like peptide 1 receptor / Glucagon-like peptide-1 receptor / GLP-1R


Mass: 14325.841 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R / Production host: Escherichia coli (E. coli) / References: UniProt: P43220
#2: Protein/peptide Semaglutide peptide backbone; 8Aib,34R-GLP-1(7-37)-OH


Mass: 3401.740 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01275*PLUS
#3: Chemical ChemComp-32M / 3,6,9,12,15,18-hexaoxahexacosan-1-ol / HEXAETHYLENE GLYCOL MONOOCTYL ETHER


Mass: 394.543 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H42O7
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.06 Å3/Da / Density % sol: 40.28 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.24 M Sodium malonate pH 7.0, 20% (w/v) PEG3350 (JCSG screen QIAGEN) and 10 mM hexaethylene glycol monooctyl ether (Detergent Screen HT Hampton Research).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.54178 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jan 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.8→28.65 Å / Num. all: 14204 / Num. obs: 14102 / % possible obs: 99.3 % / Redundancy: 8.7 % / Rmerge(I) obs: 0.049 / Net I/σ(I): 27.45
Reflection shellResolution: 1.8→1.9 Å / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 5.5 / Num. measured obs: 17121 / Num. unique all: 2028 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIXdev_1938refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3IOL

3iol


Resolution: 1.8→28.65 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1928 705 5.01 %
Rwork0.1629 --
obs0.1644 14072 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→28.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1046 0 54 88 1188
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011144
X-RAY DIFFRACTIONf_angle_d1.3461545
X-RAY DIFFRACTIONf_dihedral_angle_d15.983437
X-RAY DIFFRACTIONf_chiral_restr0.051149
X-RAY DIFFRACTIONf_plane_restr0.007194
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8001-1.9390.23261360.18272574X-RAY DIFFRACTION98
1.939-2.13410.19491390.15452634X-RAY DIFFRACTION99
2.1341-2.44280.18491390.15252628X-RAY DIFFRACTION100
2.4428-3.07710.21151410.17042704X-RAY DIFFRACTION100
3.0771-28.65390.18031500.16172827X-RAY DIFFRACTION100

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