PDB-6w9m: Structure of the Ancestral Glucocorticoid Receptor 2 ligand bindi...

ID or keywords:

Entry

Database: PDB / ID: 6w9m

Title

Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with vamorolone and SHP coregulator fragment

Components

Glucocorticoid Receptor
Nuclear receptor subfamily 0 group B member 2

Keywords

HORMONE /

Glucocorticoid Receptor / anti-inflammation drug

Function / homology

Function and homology information

bile acid and bile salt transport / transcription regulator inhibitor activity / peroxisome proliferator activated receptor binding / nuclear thyroid hormone receptor binding / animal organ regeneration / response to glucose / nuclear retinoid X receptor binding /

Notch signaling pathway / cholesterol metabolic process / circadian regulation of gene expression ...
Similarity search - Function

Biological species

synthetic construct (others)

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.59 Å

Authors

Liu, X. / Ortlund, E.A.

Funding support

United States, 2items

Organization	Grant number	Country
American Heart Association	17POST33660110	United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)	R01DK095750	United States

Citation

Journal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.
Authors: Liu, X. / Wang, Y. / Gutierrez, J.S. / Damsker, J.M. / Nagaraju, K. / Hoffman, E.P. / Ortlund, E.A.

History

Deposition	Mar 23, 2020	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Nov 4, 2020	Provider: repository / Type: Initial release
Revision 1.1	Oct 18, 2023	Group: 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

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6w9m.cif.gz	151.1 KB	Display	PDBx/mmCIF format
PDB format	pdb6w9m.ent.gz	97.3 KB	Display	PDB format
PDBx/mmJSON format	6w9m.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/w9/6w9m ftp://data.pdbj.org/pub/pdb/validation_reports/w9/6w9m	HTTPS FTP

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Related structure data

Related structure data	6w9kC 6w9lC 6nwlS S: Starting model for refinement C: citing same article (ref.)
Similar structure data	4b6g-1 3kg6-6 4xu0-1 6vc2-d 4oni-2 5il6-2 2on6-d 1il4-d 4i04-4 5ufs-1 Search similar-shape structures by Omokage search (details) Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#258 - Jun 2021 Glucocorticoid Receptor and Dexamethasone similarity (1)

Deposited unit

A: Glucocorticoid Receptor

B: Nuclear receptor subfamily 0 group B member 2

hetero molecules

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

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	87.065, 52.854, 69.646
Angle α, β, γ (deg.)	90.000, 116.394, 90.000
Int Tables number	5
Space group name H-M	C121
Space group name Hall	C2y
Symmetry operation	#1: x,y,z #2: -x,y,-z #3: x+1/2,y+1/2,z #4: -x+1/2,y+1/2,-z

#1: Protein	Glucocorticoid Receptor / / Ancestral Glucocorticoid Receptor2 Mass: 28964.703 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli) / References: UniProt: A0A1X8XLE9
#2: Protein/peptide	Nuclear receptor subfamily 0 group B member 2 / Orphan nuclear receptor SHP / Small heterodimer partner Mass: 1204.440 Da / Num. of mol.: 1 / Fragment: eleven-residue fragment / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15466
#3: Chemical	ChemComp-TUV / vamorolone / vamorolone / (8alpha,14beta,16alpha,17alpha)-17,21-dihydroxy-16-methylpregna-1,4,9(11)-triene-3,20-dione / Vamorolone Mass: 356.455 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₂H₂₈O₄ / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₃H₈O₃
#5: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 2.38 Å³/Da / Density % sol: 48.3 %
Crystal grow	Temperature: 289.15 K / Method: vapor diffusion / pH: 8.5 / Details: 25% PEG 300 and 0.1 M Tris pH 8.5

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
Detector	Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 5, 2018
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 1.586→38.995 Å / Num. obs: 38375 / % possible obs: 96.6 % / Redundancy: 5.5 % / B_iso Wilson estimate: 25.42 Å² / CC_1/2: 0.921 / Net I/σ(I): 10.9
Reflection shell	Resolution: 1.586→1.64 Å / Num. unique obs: 3352 / CC_1/2: 0.684

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Processing

Software

Name	Version	Classification
PHENIX	1.17.1_3660	refinement
HKL-2000		data reduction
HKL-2000		data scaling
HKL-2000		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 6NWL

6nwl

Resolution: 1.59→38.99 Å / SU ML: 0.223 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.3473

	R_factor	Num. reflection	% reflection
R_free	0.2197	1864	5.01 %
R_work	0.1871	-	-
obs	0.1887	37206	96.63 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å

Displacement parameters

B_iso mean: 34.54 Å²

Refinement step

Cycle: LAST / Resolution: 1.59→38.99 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2114	0	38	60	2212

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.0061	2289
X-RAY DIFFRACTION	f_angle_d	0.9062	3114
X-RAY DIFFRACTION	f_chiral_restr	0.0648	346
X-RAY DIFFRACTION	f_plane_restr	0.0046	391
X-RAY DIFFRACTION	f_dihedral_angle_d	15.1227	871

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 (%)
1.59-1.63	0.3878	121	0.3223	2358	X-RAY DIFFRACTION	85.07
1.63-1.68	0.2626	141	0.2741	2707	X-RAY DIFFRACTION	96.18
1.68-1.73	0.2778	143	0.2427	2724	X-RAY DIFFRACTION	98.05
1.73-1.79	0.2502	138	0.2158	2756	X-RAY DIFFRACTION	98.37
1.79-1.86	0.2582	147	0.2003	2743	X-RAY DIFFRACTION	97.4
1.86-1.95	0.2431	136	0.1985	2651	X-RAY DIFFRACTION	94.6
1.95-2.05	0.2382	158	0.1926	2746	X-RAY DIFFRACTION	98.57
2.05-2.18	0.2199	139	0.1809	2784	X-RAY DIFFRACTION	98.85
2.18-2.35	0.204	152	0.1775	2761	X-RAY DIFFRACTION	98.81
2.35-2.59	0.1884	146	0.1796	2778	X-RAY DIFFRACTION	98.38
2.59-2.96	0.198	146	0.1777	2710	X-RAY DIFFRACTION	95.87
2.96-3.73	0.2133	152	0.1801	2824	X-RAY DIFFRACTION	99.5
3.73-38.99	0.2207	145	0.1804	2800	X-RAY DIFFRACTION	96.43

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	6.43971274258	-6.38881857803	0.574474430455	5.60417222018	-0.452233441156	0.0622384561752	-0.0644496987832	-0.12568653673	0.196447702147	0.00416386153747	0.116009665096	-0.0726171329446	-0.0772385118995	0.0286351387254	-0.0118728379929	0.199592835345	0.0205433308892	0.0150929503223	0.187906030768	-0.00391880025211	0.268635782156	106.924900869	12.9887964361	25.2437842819
2	8.02685454963	-2.62117485761	0.161303347799	2.56256692901	-0.329995816832	1.59816291492	-0.0771307706687	-0.0691454160489	-0.180589651931	0.070050399019	0.0354104328655	0.0188166949163	0.100983157271	0.0255334054045	0.0630159207694	0.159400350563	-0.010185809536	0.0222975148741	0.109612167853	0.0187856984317	0.146192997409	101.322797805	3.83732738517	24.719378581
3	6.25841463332	2.79096040986	-2.70718830871	5.05212391269	-1.66427123642	3.24775099258	0.0870193201345	-0.201236986974	-0.0367932996346	0.00584239626405	-0.0923972117795	0.056626910546	0.0455848418649	0.0881308488778	0.0183122417909	0.199878752807	0.0259740673505	-0.0193379356697	0.172255716159	-0.00210927816927	0.186413129796	100.326844349	7.02540447055	17.8497535114
4	6.10343039232	0.613550755762	-0.183252123126	6.96828261328	0.870586173401	5.73551959572	-0.0270971438604	0.888896432347	-0.176299341411	-0.592351443187	0.128595900079	-0.288357088861	0.476969285996	0.313459998616	-0.0622801237733	0.235673539388	0.0377991337081	0.0391994675574	0.373541821985	0.00230069839919	0.25660229433	118.799078721	4.35861414121	15.2880516358
5	7.19596884818	-5.71089132419	1.83566610331	5.16423930021	-2.43353952174	2.6705628458	0.150283406216	0.298111444301	-0.0994697660566	-0.694681163995	-0.184623148001	-0.28690385171	0.43912116918	-0.247594782642	-0.00849352849728	0.370764004924	-7.08211305258E-5	0.0780335070213	0.553154094959	0.0112307435794	0.254817460578	110.888994837	8.38682207803	7.13813438181
6	7.88933630713	3.03176902525	0.480541691743	6.84842426096	0.345155785308	2.26830369997	0.0291822333182	0.089907823531	0.323803578059	-0.280479971185	-0.0799511151904	-0.115167409728	-0.223673330648	0.0826537144653	0.0452471367519	0.208977622292	0.0356583132883	0.0242201294259	0.158859468759	0.0147864334093	0.162236395663	99.1190526682	16.777647052	14.2343039531
7	3.05171920114	-4.17388774422	-3.11568382464	5.99749554721	3.53854300329	7.84538275238	-0.0418915435014	0.674289706613	-0.229849800599	-0.317090504477	-0.0643224807418	0.627081005585	0.0284512087015	-0.704618107219	0.0490680930842	0.231768004838	-0.0241996105701	-0.0750661538184	0.271890764398	0.00369106618815	0.407918330897	83.7608947672	1.38518498924	13.5673949604
8	7.34733266452	5.99369307785	-6.79008954204	5.09505438473	-5.55828104631	6.8607326665	0.0651964615386	0.433870413127	0.346569218163	-0.200725798654	0.230148156199	0.421412728287	-0.332305955048	-0.123180671601	-0.250218656112	0.274347939315	0.0869925894859	-0.00329692057939	0.244758477574	0.0145383608782	0.252324408342	89.6426036991	20.1679661196	11.769210102
9	2.31645012315	-2.81685757969	1.52941534412	8.62300883049	-4.90761630525	4.52629811581	0.310114602063	0.392687659803	-0.145416590589	-0.538246249555	-0.296097992904	0.325864693141	0.198596246765	0.310557238986	0.0141140849165	0.297838691987	0.0294916035263	0.00540402050595	0.278904758477	-0.0439459899889	0.185580352179	100.334464766	7.42433080413	6.65965375612
10	7.10673657217	0.327669529968	2.90867296467	7.63574900087	1.1799751398	7.02745668471	0.197376890111	0.00998303839726	-0.281709353557	-0.0482012703489	-0.324653153142	-0.0148386193171	0.639720405548	-0.0558209284803	0.170031952996	0.343080106398	0.0356107982294	0.0300115692516	0.159655497146	-0.0103042402345	0.279093056943	101.47668859	-8.99417728924	20.0936505388
11	3.58463249924	1.13605391898	-0.575732691316	4.87127315751	-5.65782118924	6.73320401279	-0.0555593636527	0.496033868573	-0.354539907532	-1.29945463432	-0.0860312200474	-0.203348124288	0.802970932294	-0.0173676947353	0.127394365429	0.467400715819	0.0225541744422	-0.0711818900187	0.374037610872	-0.10116655366	0.273117809195	90.4790094816	3.17795397111	4.09135731112
12	2.49991778662	-2.98978578852	2.6242278587	5.19477720505	-4.60442466862	4.82631609631	0.196260165622	-0.270292809708	-0.592146529379	0.421612273914	0.0190908971096	0.77516694059	0.184903160036	-0.886686403136	-0.211454619154	0.254939764835	-0.0433748281501	0.051573150128	0.259176871411	0.0133244124908	0.316660804859	90.6724721846	-1.12655185784	29.9368060241

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid -4 through 24 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 25 through 57 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 58 through 85 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 86 through 108 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 109 through 125 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 126 through 141 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 142 through 151 )
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 152 through 176 )
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 177 through 210 )
10	X-RAY DIFFRACTION	10	chain 'A' and (resid 211 through 234 )
11	X-RAY DIFFRACTION	11	chain 'A' and (resid 235 through 246 )
12	X-RAY DIFFRACTION	12	chain 'B' and (resid 140 through 150 )

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