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- PDB-6fx0: Structure-based design of Trifarotene (CD5789), a potent and sele... -

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Entry
Database: PDB / ID: 6fx0
TitleStructure-based design of Trifarotene (CD5789), a potent and selective RAR gamma agonist for the treatment of acne
ComponentsRetinoic acid receptor gamma
KeywordsSIGNALING PROTEIN / retinoic ligand complex / drug design / selectivity / agonist
Function / homology
Function and homology information


Harderian gland development / regulation of myeloid cell differentiation / growth plate cartilage chondrocyte growth / trachea cartilage development / embryonic eye morphogenesis / embryonic camera-type eye development / glandular epithelial cell development / prostate gland epithelium morphogenesis / positive regulation of programmed cell death / negative regulation of chondrocyte differentiation ...Harderian gland development / regulation of myeloid cell differentiation / growth plate cartilage chondrocyte growth / trachea cartilage development / embryonic eye morphogenesis / embryonic camera-type eye development / glandular epithelial cell development / prostate gland epithelium morphogenesis / positive regulation of programmed cell death / negative regulation of chondrocyte differentiation / embryonic hindlimb morphogenesis / anterior/posterior pattern specification / Signaling by Retinoic Acid / regulation of myelination / regulation of cell size / face development / canonical Wnt signaling pathway / retinoic acid receptor signaling pathway / nuclear retinoid X receptor binding / response to retinoic acid / negative regulation of stem cell proliferation / cellular response to retinoic acid / hormone-mediated signaling pathway / stem cell proliferation / cellular response to leukemia inhibitory factor / neural tube closure / multicellular organism growth / Nuclear Receptor transcription pathway / Activation of anterior HOX genes in hindbrain development during early embryogenesis / nuclear receptor activity / sequence-specific double-stranded DNA binding / transcription regulator complex / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of cell population proliferation / chromatin binding / positive regulation of cell population proliferation / positive regulation of gene expression / chromatin / apoptotic process / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / cytoplasm
Similarity search - Function
: / : / Retinoic acid receptor / Retinoid X Receptor / Retinoid X Receptor / 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. ...: / : / Retinoic acid receptor / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-E9T / Retinoic acid receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsChantalat, L. / Thoreau, E.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Structure-based design of Trifarotene (CD5789), a potent and selective RAR gamma agonist for the treatment of acne.
Authors: Thoreau, E. / Arlabosse, J.M. / Bouix-Peter, C. / Chambon, S. / Chantalat, L. / Daver, S. / Dumais, L. / Duvert, G. / Feret, A. / Ouvry, G. / Pascau, J. / Raffin, C. / Rodeville, N. / ...Authors: Thoreau, E. / Arlabosse, J.M. / Bouix-Peter, C. / Chambon, S. / Chantalat, L. / Daver, S. / Dumais, L. / Duvert, G. / Feret, A. / Ouvry, G. / Pascau, J. / Raffin, C. / Rodeville, N. / Soulet, C. / Tabet, S. / Talano, S. / Portal, T.
History
DepositionMar 8, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Retinoic acid receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9983
Polymers50,4051
Non-polymers5932
Water5,296294
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint2 kcal/mol
Surface area11870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.060, 60.060, 157.820
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Retinoic acid receptor gamma / RAR-gamma / Nuclear receptor subfamily 1 group B member 3


Mass: 50404.848 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RARG, NR1B3 / Production host: Escherichia coli (E. coli) / References: UniProt: P13631
#2: Chemical ChemComp-E9T / 6-[3-(1-adamantyl)-4-oxidanyl-phenyl]naphthalene-2-carboxylic acid


Mass: 398.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26O3
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / 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 growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: SODIUM ACETATE, PH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.934 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Mar 6, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 23093 / % possible obs: 97.7 % / Redundancy: 5.4 % / Biso Wilson estimate: 23.7 Å2 / Net I/σ(I): 39.59
Reflection shellResolution: 1.9→2.02 Å / Mean I/σ(I) obs: 15.1 / % possible all: 95.3

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→14.52 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.92 / SU R Cruickshank DPI: 0.145 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.169 / SU Rfree Blow DPI: 0.145 / SU Rfree Cruickshank DPI: 0.134
RfactorNum. reflection% reflectionSelection details
Rfree0.224 1153 5 %RANDOM
Rwork0.19 ---
obs0.191 23058 97.8 %-
Displacement parametersBiso mean: 26.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.2572 Å20 Å20 Å2
2---0.2572 Å20 Å2
3---0.5145 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: 1 / Resolution: 1.9→14.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1873 0 43 294 2210
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012011HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.972730HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d747SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes47HARMONIC2
X-RAY DIFFRACTIONt_gen_planes310HARMONIC5
X-RAY DIFFRACTIONt_it2011HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.83
X-RAY DIFFRACTIONt_other_torsion16.28
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion268SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2665SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.98 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.459 131 4.98 %
Rwork0.3499 2500 -
all0.3552 2631 -
obs--93.49 %
Refinement TLS params.Method: refined / Origin x: 19.409 Å / Origin y: -8.5874 Å / Origin z: -14.0715 Å
111213212223313233
T0.0444 Å20.0329 Å2-0.0117 Å2-0.0772 Å2-0.0082 Å2--0.0669 Å2
L0.9817 °20.4098 °2-0.3717 °2-0.6799 °2-0.2742 °2--1.5725 °2
S-0.0211 Å °-0.0059 Å °-0.0531 Å °0.0216 Å °-0.0015 Å °-0.0183 Å °-0.0197 Å °-0.108 Å °0.0225 Å °
Refinement TLS groupSelection details: { A|* }

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