PDB-6nad: Identification and biological evaluation of tertiary ALCOHOL-base...

ID or keywords:

Entry

Database: PDB / ID: 6nad

Title

Identification and biological evaluation of tertiary ALCOHOL-based inverse agonists of RORgt

Components

Nuclear receptor ROR-gamma

Keywords

NUCLEAR PROTEIN / Nuclear Receptor RORgt

Function / homology

Function and homology information

ligand-activated transcription factor activity / cellular response to sterol / T-helper 17 cell differentiation / regulation of steroid metabolic process / Peyer's patch development / positive regulation of circadian rhythm / oxysterol binding / T-helper cell differentiation / RUNX3 Regulates Immune Response and Cell Migration / negative regulation of thymocyte apoptotic process ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.90197076582 Å

Authors

Spurlino, J. / Milligan, C.

Citation

Journal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: 3-Substituted Quinolines as ROR gamma t Inverse Agonists.
Authors: Tanis, V.M. / Venkatesan, H. / Cummings, M.D. / Albers, M. / Kent Barbay, J. / Herman, K. / Kummer, D.A. / Milligan, C. / Nelen, M.I. / Nishimura, R. / Schlueter, T. / Scott, B. / Spurlino, ...

History

Deposition	Dec 5, 2018	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	May 8, 2019	Provider: repository / Type: Initial release
Revision 1.1	May 15, 2019	Group: Data collection / Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2	Mar 13, 2024	Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6nad.cif.gz	234 KB	Display	PDBx/mmCIF format
PDB format	pdb6nad.ent.gz	160.8 KB	Display	PDB format
PDBx/mmJSON format	6nad.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/na/6nad ftp://data.pdbj.org/pub/pdb/validation_reports/na/6nad	HTTPS FTP

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Related structure data

Similar structure data	6o98-2 6xfv-2 6br3-1 6b33-1 4zjr-2 3b0w-2 4zjr-1 6j1l-3 6b30-2 6b33-2 6j1l-1 6j1l-2 4wqp-2 5ayg-2 4nb6-1 Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

Similar structure data

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Links

PDB pages	PDBj / wwPDB / NCBI

Deposited unit

A: Nuclear receptor ROR-gamma

B: Nuclear receptor ROR-gamma

hetero molecules

57.9 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Nuclear receptor ROR-gamma

hetero molecules

defined by author&software
28.9 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Nuclear receptor ROR-gamma

hetero molecules

defined by author&software
28.9 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	96.742, 96.742, 127.711
Angle α, β, γ (deg.)	90.000, 90.000, 120.000
Int Tables number	169
Space group name H-M	P6₁
Space group name Hall	P6₁

#1: Protein	Nuclear receptor ROR-gamma / Nuclear receptor RZR-gamma / Nuclear receptor subfamily 1 group F member 3 / RAR-related orphan ...Nuclear receptor RZR-gamma / Nuclear receptor subfamily 1 group F member 3 / RAR-related orphan receptor C / Retinoid-related orphan receptor-gamma Mass: 28307.824 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG / Production host: Escherichia coli (E. coli) / References: UniProt: P51449
#2: Chemical	ChemComp-KHY / (S)-(4-chloro-2-methoxy-3-{[4-(trifluoromethyl)piperidin-1-yl]methyl}quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)[2-(trifluoromethyl)pyridin-4-yl]methanol Mass: 628.008 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₉H₂₈ClF₆N₅O₂

#1: Protein

Nuclear receptor ROR-gamma / Nuclear receptor RZR-gamma / Nuclear receptor subfamily 1 group F member 3 / RAR-related orphan ...

Mass: 28307.824 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: RORC, NR1F3, RORG, RZRG / Production host:

Escherichia coli (E. coli) / References: UniProt: P51449

#2: Chemical

ChemComp-KHY / (S)-(4-chloro-2-methoxy-3-{[4-(trifluoromethyl)piperidin-1-yl]methyl}quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)[2-(trifluoromethyl)pyridin-4-yl]methanol

Mass: 628.008 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₉H₂₈ClF₆N₅O₂

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 3.05 Å³/Da / Density % sol: 59.64 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion / Details: 1.35M NaFormate, 0.1M Hepes pH7, 3%MPD

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Data collection

Diffraction	Mean temperature: 80 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
Detector	Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 7, 2013
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 2.9→48.4 Å / Num. obs: 15028 / % possible obs: 99.93 % / Redundancy: 10.3 % / B_iso Wilson estimate: 94.7974713548 Å² / Χ²: 0.819 / Net I/σ(I): 30
Reflection shell	Resolution: 2.9→2.95 Å / Redundancy: 9.8 % / Num. unique obs: 745

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Processing

Software

Name	Version	Classification
PHENIX	1.12_2829	refinement
HKL-2000		data reduction
HKL-2000		data scaling
PHENIX		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.90197076582→48.371 Å / SU ML: 0.442928517367 / Cross valid method: FREE R-VALUE / σ(F): 1.36452552271 / Phase error: 25.614718559
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2

	R_factor	Num. reflection	% reflection
R_free	0.234235386697	1512	10.0612190578 %
R_work	0.176010729668	13516	-
obs	0.181943265938	15028	99.9268568389 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso mean: 96.6036987379 Å²

Refinement step

Cycle: LAST / Resolution: 2.90197076582→48.371 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3552	0	86	0	3638

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.00222034817772	3714
X-RAY DIFFRACTION	f_angle_d	0.505300024362	5012
X-RAY DIFFRACTION	f_chiral_restr	0.0338877088635	539
X-RAY DIFFRACTION	f_plane_restr	0.00170689444614	627
X-RAY DIFFRACTION	f_dihedral_angle_d	17.7355168746	2254

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2.902-2.9956	0.387432075646	140	0.295627569405	1218	X-RAY DIFFRACTION	99.9264164827
2.9956-3.1027	0.352667931511	133	0.256444414159	1231	X-RAY DIFFRACTION	99.8535871157
3.1027-3.2269	0.275839709407	136	0.218635538134	1225	X-RAY DIFFRACTION	99.8532648569
3.2269-3.3737	0.255570046532	134	0.210194858541	1213	X-RAY DIFFRACTION	100
3.3737-3.5515	0.279281050903	139	0.186190812359	1237	X-RAY DIFFRACTION	99.9273783588
3.5515-3.774	0.265717134392	134	0.182685701472	1216	X-RAY DIFFRACTION	100
3.774-4.0652	0.1981138302	141	0.144482625246	1231	X-RAY DIFFRACTION	100
4.0652-4.474	0.19619027833	137	0.14757168509	1236	X-RAY DIFFRACTION	100
4.474-5.1208	0.213049690971	135	0.152760498348	1232	X-RAY DIFFRACTION	100
5.1208-6.4493	0.266933336393	139	0.203115195289	1234	X-RAY DIFFRACTION	100
6.4493-48.3777	0.211527288292	144	0.166775420964	1243	X-RAY DIFFRACTION	99.8560115191

Refinement TLS params.

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

ID	L11 (°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)
1	2.50751145863	2.07553618786	2.60156649329	2.20411431239	5.6907893709	2.52986604227	0.13355899778	0.26421234126	0.484676032765	0.745933612154	-0.586189054884	1.58024878503	0.362734304	-0.682305675029	0.675102110987	0.798004087149	-0.148145441175	0.0952543294813	1.04837178339	-0.0589718709552	1.10297223763	101.342765578	-32.2720761592	-4.1050176992
2	3.44024417308	4.01457973557	2.27687934148	2.69267220191	2.1072391917	2.57025098874	0.621200586277	-0.416526685815	0.0736163493654	1.27651445272	-0.699238424907	-0.0435571994411	0.405999914623	-0.193956474348	0.0578855476627	0.84366845864	-0.0330116029182	0.194582362946	0.684566875771	-0.041927158199	0.988453158451	115.821885517	-23.6071674357	8.26039384816
3	8.14009144261	-3.38250613249	1.57314477733	6.7858836083	0.0519540708708	9.08919245363	0.247224885618	-0.85597086099	-0.559823527665	0.475142215446	-0.590316203865	-0.557478777013	1.69254957829	0.186865716311	0.108026362711	0.974611174218	-0.151250403458	0.0830252111532	0.710621091322	-0.039981274173	0.531466422204	111.758983058	-42.1077411592	3.67825558338
4	2.26045188164	1.75446330519	0.797822116275	3.86925577185	1.37702742114	1.28502827998	0.0464514596543	0.155361084725	-0.10169517591	0.0326877383152	-0.163993150462	-0.0703184695248	0.0839040443595	-0.00360978193186	0.0784609656556	0.739022262072	-0.0375689934898	0.120673558669	0.719502104251	0.0791246879437	0.663536712696	113.808792369	-34.83783773	-5.39777082834
5	4.59200942958	-2.32047080677	-6.50535405324	8.9516638527	1.18752105981	9.90728526505	-0.445643516256	0.272056477481	-0.479793572739	-0.0173005313933	-0.118037021369	0.111719395049	0.433976542099	0.774890783819	0.503903102058	0.783152455911	-0.0242357277495	0.0900068356517	0.901985641548	0.000391938316095	0.547425991009	111.548503007	-38.2974365584	-17.1658922105
6	4.78024461664	5.21311161758	5.76833064605	5.62349245364	6.2432969843	6.81468807419	1.06993719729	1.24684633615	-1.73622076231	0.871023737635	0.771871828515	-1.88447205186	0.945708775358	1.75040791125	-2.1825003488	1.16898849205	0.393494074357	0.042383005214	1.91253002859	0.0706486746637	1.3496992162	126.023889952	-34.7441372481	2.79408102994
7	7.73043488028	-7.38738882075	6.09530101322	7.02012968923	-5.88430409572	4.80666229891	-1.24182495096	1.20617291492	2.97304103402	0.014887091951	-0.251517844714	-1.26702122561	-1.6627070107	0.967932798607	1.39634809001	0.846273234713	-0.104745697301	-0.00891763057796	0.857928727488	0.187074119905	1.00139403651	131.717707839	-28.5250841112	37.0864437918
8	4.57171965915	-4.42927034424	-0.598692864014	4.38117411644	-0.089755676004	1.9066730935	0.173894947974	0.488339628903	1.06711177593	-0.191493758454	-0.301338002102	-0.0942533636049	-0.234256257793	0.0482916451165	0.10620128205	0.609090912268	-0.000867752751162	0.0192035427551	0.627100448522	0.0828081148188	0.655895448279	105.179233234	-25.9494900205	26.4118978994
9	9.50740378262	-5.48849991919	0.282666276676	4.98594199426	2.29218390175	4.34152506793	-0.217034178474	0.798531980749	0.571965152493	0.21518917945	0.20606678295	-0.205531599405	1.10908546188	0.915031758962	0.0359284990596	0.752703326483	0.0190103756445	0.0183118964673	1.03068968471	0.177262351409	0.734587012193	120.89569633	-37.3748892619	26.8814502615
10	6.49143769174	-1.49004840773	2.81399919275	0.180610943737	-1.31494583984	2.32240034134	0.0997515062238	-0.184301996919	-0.243290146856	-0.00919863569399	-0.0876129563202	0.286827415928	0.111875837505	-0.0950337438193	0.0101908166819	0.743800097413	0.00327528667476	-0.0227542472207	0.713882689963	0.00415977861182	0.780793048375	114.601975255	-34.8725221112	37.4538951113
11	1.30529089125	1.8510535775	2.64800017694	4.31527955757	5.08313696338	7.95312907541	1.36489080963	0.664066167162	-0.570120363336	-1.11964315067	-0.367999060083	1.38317939501	2.27543577275	2.06482025171	-1.02072887986	2.37301179656	0.251565244028	-0.332140677141	0.827913038937	-0.0649948322943	1.17388852425	109.970776278	-43.9055900785	34.8638781392

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 265 through 301 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 302 through 337 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 338 through 368 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 369 through 456 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 457 through 469 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 470 through 485 )
7	X-RAY DIFFRACTION	7	chain 'B' and (resid 265 through 282 )
8	X-RAY DIFFRACTION	8	chain 'B' and (resid 283 through 337 )
9	X-RAY DIFFRACTION	9	chain 'B' and (resid 338 through 368 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 369 through 465 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 466 through 479 )

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