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- PDB-4phu: Crystal structure of Human GPR40 bound to allosteric agonist TAK-875 -

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Basic information

Entry
Database: PDB / ID: 4phu
TitleCrystal structure of Human GPR40 bound to allosteric agonist TAK-875
ComponentsFree fatty acid receptor 1,Lysozyme
KeywordsFatty acid binding protein/Hydrolase / GPR40 / fatty acid binding protein / class A / g-protein coupled receptor / type II diabetes / TAK-875 / fasiglifam / Fatty acid binding protein-Hydrolase complex
Function / homology
Function and homology information


bioactive lipid receptor activity / Free fatty acid receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / ion channel modulating, G protein-coupled receptor signaling pathway / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / response to fatty acid / positive regulation of calcium ion transport / insulin secretion / negative regulation of interleukin-1 beta production / ligand-gated ion channel signaling pathway ...bioactive lipid receptor activity / Free fatty acid receptors / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / ion channel modulating, G protein-coupled receptor signaling pathway / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / response to fatty acid / positive regulation of calcium ion transport / insulin secretion / negative regulation of interleukin-1 beta production / ligand-gated ion channel signaling pathway / viral release from host cell by cytolysis / peptidoglycan catabolic process / G protein-coupled receptor activity / positive regulation of insulin secretion / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / cell wall macromolecule catabolic process / lysozyme / glucose homeostasis / lysozyme activity / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (q) signalling events / host cell cytoplasm / defense response to bacterium / G protein-coupled receptor signaling pathway / lipid binding / plasma membrane
Similarity search - Function
GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. ...GPR40 receptor fatty acid / G protein-coupled receptor 40-related receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Lysozyme-like domain superfamily
Similarity search - Domain/homology
Chem-2YB / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Free fatty acid receptor 1 / Endolysin
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.332 Å
AuthorsSrivastava, A. / Yano, J.K. / Hirozane, Y. / Kefala, G. / Snell, G. / Lane, W. / Gruswitz, F. / Ivetac, A. / Aertgeerts, K. / Nguyen, J. ...Srivastava, A. / Yano, J.K. / Hirozane, Y. / Kefala, G. / Snell, G. / Lane, W. / Gruswitz, F. / Ivetac, A. / Aertgeerts, K. / Nguyen, J. / Jennings, A. / Okada, K.
CitationJournal: Nature / Year: 2014
Title: High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875.
Authors: Srivastava, A. / Yano, J. / Hirozane, Y. / Kefala, G. / Gruswitz, F. / Snell, G. / Lane, W. / Ivetac, A. / Aertgeerts, K. / Nguyen, J. / Jennings, A. / Okada, K.
History
DepositionMay 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 16, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 23, 2014Group: Database references
Revision 1.2Aug 6, 2014Group: Database references
Revision 1.3Oct 1, 2014Group: Database references
Revision 1.4Feb 4, 2015Group: Derived calculations
Revision 1.5Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.6Sep 27, 2023Group: 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 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Free fatty acid receptor 1,Lysozyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,7269
Polymers53,1021
Non-polymers2,6248
Water1,62190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.000, 61.740, 105.700
Angle α, β, γ (deg.)90.000, 108.900, 90.000
Int Tables number5
Space group name H-MC121
Detailsbiological unit is the same as asym.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Free fatty acid receptor 1,Lysozyme / G-protein coupled receptor 40 / Endolysin / Lysis protein / Muramidase


Mass: 53102.188 Da / Num. of mol.: 1
Fragment: UNP O14842 residues 2-213, UNP P00720 residues 2-161, UNP O14842 residues 214-300
Mutation: L42A,F88A,G103A,Y202F,S211G,G212S,C1154T,C1197A
Source method: isolated from a genetically manipulated source
Details: Chimera
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: FFAR1, GPR40, E / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9 / References: UniProt: O14842, UniProt: P00720, lysozyme

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Non-polymers , 5 types, 98 molecules

#2: Chemical ChemComp-2YB / [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid


Mass: 524.625 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32O7S
#3: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C21H40O4
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / Source method: isolated from a natural source / Formula: H2O

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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

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
12.9458.1
2
Crystal grow
Temperature (K)Crystal-IDMethodpHDetails
2941lipidic cubic phase829-31% Peg 400,100 mM Tris pH 8.0. 0.2 M Na Malonate,200 uM TAK-875
2942lipidic cubic phase7.239.8 % Peg 400, 100 mM Bis-Tris-Propane pH 7.2, 0.1 Ammonium Phosphate (monobasic), 200 uM TAK-875

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONALS 5.0.310.976
SYNCHROTRONAPS 23-ID-B21
Detector
TypeIDDetectorDate
ADSC QUANTUM 315r1CCDMay 22, 2012
MARMOSAIC 300 mm CCD2CCDJun 5, 2012
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1Si(220)SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray2
Radiation wavelength
IDWavelength (Å)Relative weight
10.9761
211
ReflectionResolution: 2.33→100 Å / Num. all: 26022 / Num. obs: 26022 / % possible obs: 98.2 % / Redundancy: 5 % / Rpim(I) all: 0.056 / Rrim(I) all: 0.133 / Rsym value: 0.12 / Net I/av σ(I): 4.538 / Net I/σ(I): 8.3 / Num. measured all: 129016
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.33-2.463.40.62311192635060.3490.623290
2.46-2.613.70.471.41307435470.260.472.898.7
2.61-2.794.60.3631.81578433950.1810.3634.199.5
2.79-3.015.50.2842.51763131790.1320.2845.7100
3.01-3.35.50.1883.71638929680.0880.1888.2100
3.3-3.695.80.1344.91523726430.0610.13411.899.9
3.69-4.265.90.0986.61397623580.0430.09815.499.9
4.26-5.215.70.0846.61130319880.0360.08417.199.8
5.21-7.375.70.0738.4890115700.0330.07316.399.9
7.37-30.0255.50.05410.947958680.0250.0541998.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
MOLREP10.2.35phasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.14data extraction
Coot0.7model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EJ4

4ej4


Resolution: 2.332→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.93 / SU B: 14.734 / SU ML: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.272 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2331 1312 5.1 %RANDOM
Rwork0.1981 24635 --
obs0.1999 25947 97.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 104.16 Å2 / Biso mean: 48.541 Å2 / Biso min: 16.45 Å2
Baniso -1Baniso -2Baniso -3
1-2.17 Å20 Å2-0.24 Å2
2---0.55 Å20 Å2
3----1.18 Å2
Refinement stepCycle: final / Resolution: 2.332→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3272 0 127 90 3489
Biso mean--58.72 47.69 -
Num. residues----434
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193495
X-RAY DIFFRACTIONr_bond_other_d0.0010.023421
X-RAY DIFFRACTIONr_angle_refined_deg1.1181.9954739
X-RAY DIFFRACTIONr_angle_other_deg0.74337832
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9785438
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.67922.258124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.26315511
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9691523
X-RAY DIFFRACTIONr_chiral_restr0.0620.2531
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213884
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02808
X-RAY DIFFRACTIONr_mcbond_it1.1042.5381740
X-RAY DIFFRACTIONr_mcbond_other1.1032.5371739
X-RAY DIFFRACTIONr_mcangle_it1.8943.7982173
LS refinement shellResolution: 2.332→2.392 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 67 -
Rwork0.267 1493 -
all-1560 -
obs--79.51 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5093-0.1434-0.05493.00020.27962.0220.02520.0435-0.0150.0042-0.03830.02750.0545-0.18180.01310.0340.00360.02450.13010.00020.0191-40.2690.62351.538
20.8935-0.50721.61921.0345-0.45888.49490.10860.1813-0.0931-0.0555-0.04630.07180.5592-0.7243-0.06230.1519-0.05720.08460.4986-0.04550.0981-10.522-4.0527.14
32.37130.2551-0.60250.9182-0.01583.0061-0.05160.15770.105-0.0759-0.0678-0.1529-0.1490.26410.11940.06870.00290.04380.17640.01870.0857-29.2210.36748.14
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A15 - 211
2X-RAY DIFFRACTION2A1002 - 1161
3X-RAY DIFFRACTION3A2214 - 2280

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