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- PDB-6ivx: Discovery of the Second Generation ROR gamma Inhibitors Composed ... -

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Basic information

Entry
Database: PDB / ID: 6ivx
TitleDiscovery of the Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.
Components
  • Nuclear receptor ROR-gamma
  • Nuclear receptor corepressor 2
KeywordsNUCLEAR PROTEIN/INHIBITOR / Ternary Complex / Nuclear Receptor / NUCLEAR PROTEIN / NUCLEAR PROTEIN-INHIBITOR complex / IMMUNE SYSTEM
Function / homology
Function and homology information


Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of ketone metabolic process / nuclear glucocorticoid receptor binding / cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-modulated transcription factor activity / negative regulation of androgen receptor signaling pathway / Peyer's patch development / positive regulation of circadian rhythm ...Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of ketone metabolic process / nuclear glucocorticoid receptor binding / cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / ligand-modulated transcription factor activity / negative regulation of androgen receptor signaling pathway / Peyer's patch development / positive regulation of circadian rhythm / T-helper cell differentiation / RUNX3 Regulates Immune Response and Cell Migration / oxysterol binding / negative regulation of thymocyte apoptotic process / Notch binding / regulation of fat cell differentiation / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / regulation of glucose metabolic process / Regulation of MECP2 expression and activity / adipose tissue development / lymph node development / estrous cycle / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / lactation / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / xenobiotic metabolic process / SUMOylation of transcription cofactors / negative regulation of miRNA transcription / cerebellum development / HDACs deacetylate histones / circadian regulation of gene expression / Downregulation of SMAD2/3:SMAD4 transcriptional activity / enzyme activator activity / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / DNA-binding transcription repressor activity, RNA polymerase II-specific / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / nuclear matrix / nuclear receptor activity / HCMV Early Events / sequence-specific double-stranded DNA binding / transcription corepressor activity / response to estradiol / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / protein-containing complex binding / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus / membrane
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Nuclear receptor ROR / Retinoid-related orphan receptors, DNA-binding domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Retinoid X Receptor / Retinoid X Receptor / Homeobox-like domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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-AYO / Nuclear receptor ROR-gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsNoguchi, M. / Nomura, A. / Doi, S. / Adachi, T.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Discovery of Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.
Authors: Kotoku, M. / Maeba, T. / Fujioka, S. / Yokota, M. / Seki, N. / Ito, K. / Suwa, Y. / Ikenogami, T. / Hirata, K. / Hase, Y. / Katsuda, Y. / Miyagawa, N. / Arita, K. / Asahina, K. / Noguchi, M. ...Authors: Kotoku, M. / Maeba, T. / Fujioka, S. / Yokota, M. / Seki, N. / Ito, K. / Suwa, Y. / Ikenogami, T. / Hirata, K. / Hase, Y. / Katsuda, Y. / Miyagawa, N. / Arita, K. / Asahina, K. / Noguchi, M. / Nomura, A. / Doi, S. / Adachi, T. / Crowe, P. / Tao, H. / Thacher, S. / Hashimoto, H. / Suzuki, T. / Shiozaki, M.
History
DepositionDec 4, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 6, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 27, 2019Group: Data collection / 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 1.3Nov 22, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nuclear receptor ROR-gamma
B: Nuclear receptor corepressor 2
C: Nuclear receptor ROR-gamma
D: Nuclear receptor corepressor 2
E: Nuclear receptor ROR-gamma
F: Nuclear receptor corepressor 2
G: Nuclear receptor ROR-gamma
H: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,55512
Polymers129,4178
Non-polymers2,1384
Water27015
1
A: Nuclear receptor ROR-gamma
B: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8893
Polymers32,3542
Non-polymers5341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint-10 kcal/mol
Surface area12460 Å2
MethodPISA
2
C: Nuclear receptor ROR-gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8893
Polymers32,3542
Non-polymers5341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint-8 kcal/mol
Surface area12440 Å2
MethodPISA
3
E: Nuclear receptor ROR-gamma
F: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8893
Polymers32,3542
Non-polymers5341
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1440 Å2
ΔGint-10 kcal/mol
Surface area12560 Å2
MethodPISA
4
G: Nuclear receptor ROR-gamma
H: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8893
Polymers32,3542
Non-polymers5341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-12 kcal/mol
Surface area12490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.285, 72.555, 98.880
Angle α, β, γ (deg.)90.00, 90.01, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12A
22E
13A
23G
14B
24F
15B
25H
16C
26E
17C
27G
18E
28G
19F
29H

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERILEILEAA266 - 4926 - 232
21SERSERILEILECC266 - 4926 - 232
12SERSERILEILEAA266 - 4926 - 232
22SERSERILEILEEE266 - 4926 - 232
13SERSERILEILEAA266 - 4926 - 232
23SERSERILEILEGG266 - 4926 - 232
14THRTHRMETMETBB2346 - 23591 - 14
24THRTHRMETMETFF2346 - 23591 - 14
15ASNASNLEULEUBB2347 - 23582 - 13
25ASNASNLEULEUHH2347 - 23582 - 13
16SERSERILEILECC266 - 4926 - 232
26SERSERILEILEEE266 - 4926 - 232
17SERSERILEILECC266 - 4926 - 232
27SERSERILEILEGG266 - 4926 - 232
18SERSERILEILEEE266 - 4926 - 232
28SERSERILEILEGG266 - 4926 - 232
19ASNASNLEULEUFF2347 - 23582 - 13
29ASNASNLEULEUHH2347 - 23582 - 13

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9

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Components

#1: Protein
Nuclear receptor ROR-gamma / Retinoid-related orphan receptor-gamma


Mass: 29754.301 Da / Num. of mol.: 4 / Mutation: K469A, R473A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RORG / Production host: Escherichia coli (E. coli) / References: UniProt: P51449
#2: Protein/peptide
Nuclear receptor corepressor 2 / SMRT


Mass: 2599.999 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOR2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y618
#3: Chemical
ChemComp-AYO / (4S)-4-[4'-cyclopropyl-5-(2,2-dimethylpropyl)[3,5'-bi-1,2-oxazol]-3'-yl]-6-[(2,4-dichlorophenyl)amino]-6-oxohexanoic acid


Mass: 534.432 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H29Cl2N3O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / 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

CrystalDensity Matthews: 2.2 Å3/Da / Density % sol: 44.03 %
Crystal growTemperature: 299 K / Method: vapor diffusion, sitting drop / pH: 6.9 / Details: 0.1M MES pH6.0, 10% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-1A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Oct 26, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.588
11-h,-k,l20.412
ReflectionResolution: 2.35→72.56 Å / Num. obs: 46027 / % possible obs: 98.1 % / Redundancy: 3.1 % / CC1/2: 0.994 / Net I/σ(I): 7.7
Reflection shellResolution: 2.35→2.43 Å / Num. unique obs: 14914 / CC1/2: 0.79 / % possible all: 98.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5x8q

5x8q


Resolution: 2.35→53.53 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.955 / SU B: 4.099 / SU ML: 0.104 / Cross valid method: FREE R-VALUE / ESU R: 0.075 / ESU R Free: 0.043
Details: SF FILE CONTAINS FRIEDEL PAIRS UNDER I/F_MINUS AND I/F_PLUS COLUMNS. HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19841 2227 4.8 %RANDOM
Rwork0.182 ---
obs0.18283 43777 97.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 53.268 Å2
Baniso -1Baniso -2Baniso -3
1--43.64 Å2-0 Å20.08 Å2
2--65.18 Å20 Å2
3----21.54 Å2
Refinement stepCycle: 1 / Resolution: 2.35→53.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7771 0 144 15 7930
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0138074
X-RAY DIFFRACTIONr_bond_other_d0.0040.0177562
X-RAY DIFFRACTIONr_angle_refined_deg1.6321.65910873
X-RAY DIFFRACTIONr_angle_other_deg1.2841.5917478
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3615948
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.12621.198459
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.326151484
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2271568
X-RAY DIFFRACTIONr_chiral_restr0.0760.21000
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.028888
X-RAY DIFFRACTIONr_gen_planes_other0.0080.021784
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it6.4415.4183819
X-RAY DIFFRACTIONr_mcbond_other6.4345.4173818
X-RAY DIFFRACTIONr_mcangle_it8.2828.1374758
X-RAY DIFFRACTIONr_mcangle_other8.2838.1384759
X-RAY DIFFRACTIONr_scbond_it7.025.9664255
X-RAY DIFFRACTIONr_scbond_other7.025.9684256
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.4598.736104
X-RAY DIFFRACTIONr_long_range_B_refined12.7932027
X-RAY DIFFRACTIONr_long_range_B_other12.79232026
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A71800.09
12C71800.09
21A71310.08
22E71310.08
31A71490.08
32G71490.08
41B3490.13
42F3490.13
51B2810.19
52H2810.19
61C71950.08
62E71950.08
71C71880.09
72G71880.09
81E71790.07
82G71790.07
91F2800.18
92H2800.18
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 171 -
Rwork0.266 3207 -
obs--98.06 %

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