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- PDB-7d42: Structural basis of tropifexor as a potent and selective agonist ... -

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Basic information

Entry
Database: PDB / ID: 7d42
TitleStructural basis of tropifexor as a potent and selective agonist for farnesoid X receptor
Components
  • Bile acid receptor
  • Peptide from Nuclear receptor coactivator 2
KeywordsNUCLEAR PROTEIN / farnesoid X receptor / tropifexor
Function / homology
Function and homology information


regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / : / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid ...regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / : / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / : / toll-like receptor 9 signaling pathway / intracellular receptor signaling pathway / negative regulation of monocyte chemotactic protein-1 production / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / bile acid binding / cell-cell junction assembly / bile acid signaling pathway / cellular response to fatty acid / negative regulation of interleukin-2 production / regulation of cholesterol metabolic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / positive regulation of interleukin-17 production / intracellular glucose homeostasis / locomotor rhythm / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / aryl hydrocarbon receptor binding / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / negative regulation of tumor necrosis factor-mediated signaling pathway / Synthesis of bile acids and bile salts / fatty acid homeostasis / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / positive regulation of insulin receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / Notch signaling pathway / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / transcription coregulator binding / response to progesterone / cholesterol homeostasis / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / euchromatin / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / cell differentiation / receptor complex / nuclear body / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / defense response to bacterium / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / innate immune response / chromatin binding
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type
Similarity search - Domain/homology
Tropifexor / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.697 Å
AuthorsJiang, L. / Chen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81570537 and 81974074 China
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2021
Title: Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor.
Authors: Jiang, L. / Xiao, D. / Li, Y. / Dai, S. / Qu, L. / Chen, X. / Guo, M. / Wei, H. / Chen, Y.
History
DepositionSep 22, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.name
Revision 1.2Nov 29, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile acid receptor
B: Peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,1953
Polymers30,5912
Non-polymers6041
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area860 Å2
ΔGint-9 kcal/mol
Surface area11400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.539, 158.539, 158.539
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number196
Space group name H-MF23

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Components

#1: Protein Bile acid receptor / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H ...Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H member 4 / Retinoid X receptor-interacting protein 14 / RXR-interacting protein 14


Mass: 28882.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96RI1
#2: Protein/peptide Peptide from Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1708.931 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOA2, BHLHE75, SRC2, TIF2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15596
#3: Chemical ChemComp-GWF / Tropifexor


Mass: 603.585 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H25F4N3O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
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: 2.71 Å3/Da / Density % sol: 54.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 100mM Sodium acetate pH 4.7, 2.3-2.6M Sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97915 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.697→50 Å / Num. obs: 17348 / % possible obs: 97.67 % / Redundancy: 37 % / CC1/2: 0.998 / Rmerge(I) obs: 0.147 / Rrim(I) all: 0.1492 / Net I/σ(I): 18.92
Reflection shellResolution: 2.697→2.792 Å / Rmerge(I) obs: 2.672 / Mean I/σ(I) obs: 2.41 / Num. unique obs: 890 / CC1/2: 0.658

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3dct

3dct


Resolution: 2.697→45.766 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.269 1752 10.16 %
Rwork0.2189 15494 -
obs0.2241 17326 97.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 175.12 Å2 / Biso mean: 93.0325 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.697→45.766 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1832 0 42 0 1874
Biso mean--82.78 --
Num. residues----236
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051929
X-RAY DIFFRACTIONf_angle_d0.8942634
X-RAY DIFFRACTIONf_chiral_restr0.038306
X-RAY DIFFRACTIONf_plane_restr0.005334
X-RAY DIFFRACTIONf_dihedral_angle_d6.3921176
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.697-2.76970.35451280.2844117699
2.7697-2.85120.32921440.26131272100
2.8512-2.94320.3221380.29091213100
2.9432-3.04840.33221260.26561233100
3.0484-3.17040.35021280.27781236100
3.1704-3.31470.34541400.28611237100
3.3147-3.48940.37551360.30981222100
3.4894-3.70790.3441330.3051107589
3.7079-3.9940.22071050.240192074
3.994-4.39570.23531360.19751217100
4.3957-5.0310.28641500.18211228100
5.031-6.33590.28621400.22371232100
6.3359-45.7660.19461480.16411233100
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)
11.0757-0.7595-0.35460.19570.21880.5267-1.0969-2.26191.20241.69960.3382-0.3528-0.32682.07030.01991.0195-0.1958-0.01631.13120.22891.658319.491511.678-44.9352
20.8274-0.6648-1.28240.38680.40661.35530.28340.682-0.26530.2370.1919-0.67690.2371.3110.02380.82440.0679-0.05530.96770.02241.107428.0274-17.4026-43.5012
31.5511-0.00710.62140.7113-0.11571.7867-0.23290.35370.46451.09020.641-0.56420.10760.87220.02820.51570.05670.05150.52670.09680.542122.1266-10.8531-36.1079
42.3827-0.1352-0.18430.48590.12430.1182-0.1842-2.30833.15462.04160.4429-1.6262-0.2704-0.8823-0.00541.1789-0.0073-0.09260.6102-0.21241.452416.30489.2707-29.2813
50.5531-1.46651.29583.80482.35882.96980.39140.09480.6471.0522-0.6667-1.09861.4425-0.27160.0230.23730.34590.14540.70690.05560.563414.1372-4.5292-37.3811
63.4361-2.63812.35492.83990.45942.56630.8270.71630.0015-0.2086-1.0253-0.3021-0.35030.084-0.01020.95320.3014-0.03870.8019-0.1350.652212.9348-17.7079-47.4886
72.5034-1.02111.93195.4232-0.00831.61490.0540.62010.92150.21720.093-0.2562-0.7352-0.22270.00120.53180.07260.01770.67580.2140.80158.83335.8523-42.5558
81.3322-0.77411.43030.3212-0.34960.33120.47630.4251-0.4893-0.4296-0.33771.01390.1612-0.4808-0.00530.73810.14850.03850.78430.11920.56795.4621-9.5859-39.7365
90.70570.3189-0.54870.4084-0.0340.3595-0.857-1.4554-1.01460.89820.19611.31330.31780.5242-0.00210.68770.07230.00330.61150.0290.701817.1653-15.4696-27.4476
101.8556-0.19021.47361.5497-0.78541.4244-1.4853-0.71410.54323.91160.9303-0.5391-3.6423-0.5545-0.05490.7236-0.0331-0.67160.8287-0.11041.255822.3635-2.531-22.9524
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 245 through 261 )A245 - 261
2X-RAY DIFFRACTION2chain 'A' and (resid 262 through 279 )A262 - 279
3X-RAY DIFFRACTION3chain 'A' and (resid 280 through 304 )A280 - 304
4X-RAY DIFFRACTION4chain 'A' and (resid 305 through 312 )A305 - 312
5X-RAY DIFFRACTION5chain 'A' and (resid 313 through 338 )A313 - 338
6X-RAY DIFFRACTION6chain 'A' and (resid 339 through 374 )A339 - 374
7X-RAY DIFFRACTION7chain 'A' and (resid 375 through 426 )A375 - 426
8X-RAY DIFFRACTION8chain 'A' and (resid 427 through 457 )A427 - 457
9X-RAY DIFFRACTION9chain 'A' and (resid 458 through 470 )A458 - 470
10X-RAY DIFFRACTION10chain 'B' and (resid 745 through 755 )B745 - 755

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