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- PDB-6w2j: CPS1 bound to allosteric inhibitor H3B-374 -

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Basic information

Entry
Database: PDB / ID: 6w2j
TitleCPS1 bound to allosteric inhibitor H3B-374
ComponentsCarbamoyl-phosphate synthase [ammonia], mitochondrial
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


carbamoyl phosphate biosynthetic process / cellular response to oleic acid / monoatomic anion homeostasis / triglyceride catabolic process / modified amino acid binding / carbamoyl-phosphate synthase (ammonia) / carbamoyl-phosphate synthase (ammonia) activity / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / homocysteine metabolic process / cellular response to ammonium ion ...carbamoyl phosphate biosynthetic process / cellular response to oleic acid / monoatomic anion homeostasis / triglyceride catabolic process / modified amino acid binding / carbamoyl-phosphate synthase (ammonia) / carbamoyl-phosphate synthase (ammonia) activity / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / homocysteine metabolic process / cellular response to ammonium ion / Urea cycle / citrulline biosynthetic process / urea cycle / hepatocyte differentiation / cellular response to fibroblast growth factor stimulus / response to growth hormone / glutamate binding / response to food / midgut development / nitric oxide metabolic process / response to zinc ion / glutamine metabolic process / response to dexamethasone / cellular response to glucagon stimulus / mitochondrial nucleoid / response to amine / response to starvation / potassium ion binding / small molecule binding / response to amino acid / 'de novo' pyrimidine nucleobase biosynthetic process / cellular response to cAMP / response to toxic substance / phospholipid binding / vasodilation / endopeptidase activity / response to lipopolysaccharide / mitochondrial inner membrane / mitochondrial matrix / response to xenobiotic stimulus / calcium ion binding / protein-containing complex binding / nucleolus / protein-containing complex / ATP binding / metal ion binding / plasma membrane / cytoplasm
Similarity search - Function
Carbamoyl-phosphate synthase small subunit, N-terminal domain / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain / Carbamoyl-phosphate synthase large subunit, CPSase domain / Carbamoyl-phosphate synthase, small subunit / Carbamoyl-phosphate synthase, large subunit / Carbamoyl-phosphate synthase small subunit, GATase1 domain / Carbamoyl-phosphate synthase small subunit, N-terminal domain superfamily / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain superfamily / Carbamoyl-phosphate synthase small chain, CPSase domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain ...Carbamoyl-phosphate synthase small subunit, N-terminal domain / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain / Carbamoyl-phosphate synthase large subunit, CPSase domain / Carbamoyl-phosphate synthase, small subunit / Carbamoyl-phosphate synthase, large subunit / Carbamoyl-phosphate synthase small subunit, GATase1 domain / Carbamoyl-phosphate synthase small subunit, N-terminal domain superfamily / Carbamoyl-phosphate synthetase, large subunit oligomerisation domain superfamily / Carbamoyl-phosphate synthase small chain, CPSase domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain / Carbamoyl-phosphate synthetase large chain, oligomerisation domain / Carbamoyl-phosphate synthase small chain, CPSase domain / MGS-like domain profile. / Methylglyoxal synthase-like domain / Methylglyoxal synthase-like domain superfamily / MGS-like domain / MGS-like domain / Glutamine amidotransferase class-I / Glutamine amidotransferase / Carbamoyl-phosphate synthase subdomain signature 1. / Glutamine amidotransferase type 1 domain profile. / Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain / Carbamoyl-phosphate synthase L chain, ATP binding domain / ATP-grasp fold, subdomain 1 / Pre-ATP-grasp domain superfamily / ATP-grasp fold / ATP-grasp fold profile. / Class I glutamine amidotransferase-like / Carbamoyl-phosphate synthase subdomain signature 2.
Similarity search - Domain/homology
Chem-374 / Carbamoyl-phosphate synthase [ammonia], mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.62 Å
AuthorsLarsen, N.A. / Nguyen, T.V.
Citation
#1: Journal: Cell Chem Biol / Year: 2020
Title: Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.
Authors: Yao, S. / Nguyen, T.V. / Rolfe, A. / Agrawal, A.A. / Ke, J. / Peng, S. / Colombo, F. / Yu, S. / Bouchard, P. / Wu, J. / Huang, K.C. / Bao, X. / Omoto, K. / Selvaraj, A. / Yu, L. / Ioannidis, ...Authors: Yao, S. / Nguyen, T.V. / Rolfe, A. / Agrawal, A.A. / Ke, J. / Peng, S. / Colombo, F. / Yu, S. / Bouchard, P. / Wu, J. / Huang, K.C. / Bao, X. / Omoto, K. / Selvaraj, A. / Yu, L. / Ioannidis, S. / Vaillancourt, F.H. / Zhu, P. / Larsen, N.A. / Bolduc, D.M.
History
DepositionMar 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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: Carbamoyl-phosphate synthase [ammonia], mitochondrial
B: Carbamoyl-phosphate synthase [ammonia], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)331,2877
Polymers330,2572
Non-polymers1,0305
Water2,450136
1
A: Carbamoyl-phosphate synthase [ammonia], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,6744
Polymers165,1291
Non-polymers5463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Carbamoyl-phosphate synthase [ammonia], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,6123
Polymers165,1291
Non-polymers4842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.660, 98.530, 142.530
Angle α, β, γ (deg.)102.130, 97.940, 106.110
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Carbamoyl-phosphate synthase [ammonia], mitochondrial / Carbamoyl-phosphate synthetase I / CPSase I


Mass: 165128.531 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CPS1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31327, carbamoyl-phosphate synthase (ammonia)
#2: Chemical ChemComp-374 / (2-fluoranyl-4-methoxy-phenyl)-[(3~{R},5~{R})-4-(2-fluoranyl-4-methoxy-phenyl)carbonyl-3,5-dimethyl-piperazin-1-yl]methanone


Mass: 418.434 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24F2N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / Source method: isolated from a natural source / Formula: H2O
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: 2.8 Å3/Da / Density % sol: 56.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: CPS1 protein was buffer exchanged into 50 mM glycyl-glycine pH 7.4, 50 mM KCl, 5% glycerol. CPS1 was concentrated to 10 mg/ml and H3B-4193 was added to a 5x excess molar ratio along with 1mM ...Details: CPS1 protein was buffer exchanged into 50 mM glycyl-glycine pH 7.4, 50 mM KCl, 5% glycerol. CPS1 was concentrated to 10 mg/ml and H3B-4193 was added to a 5x excess molar ratio along with 1mM AMPPNP and 1mM NAG. Ligand bound complex crystals grew by hanging drop vapor diffusion in 20% PEG 3350 and 0.2M trisodium citrate

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Data collection

DiffractionMean temperature: 120 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Mar 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.62→58.96 Å / Num. obs: 104121 / % possible obs: 96.6 % / Redundancy: 2.051 % / Biso Wilson estimate: 49.396 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.072 / Rrim(I) all: 0.098 / Χ2: 0.983 / Net I/σ(I): 9.35 / Num. measured all: 213566 / Scaling rejects: 30
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.62-2.692.1130.5231.6816309801677180.6880.71196.3
2.69-2.762.1140.4292.0316002781875690.7630.58396.8
2.76-2.842.1130.3512.415447753773090.8140.47697
2.84-2.932.0910.2992.814818729470860.8550.40697.1
2.93-3.032.090.2343.5614407709268940.910.31797.2
3.03-3.132.1020.1854.4414052691366850.9420.2596.7
3.13-3.252.0640.1525.2713403666664940.9570.20597.4
3.25-3.382.0880.1146.7212781636961210.9770.15496.1
3.38-3.532.0230.0928.1211879609158720.9840.12596.4
3.53-3.712.0060.0710.2911237587156020.990.09595.4
3.71-3.911.9340.05911.8410353555553520.9930.0896.3
3.91-4.141.7760.04813.59035527850870.9950.06596.4
4.14-4.431.8520.03916.348823496847650.9960.05295.9
4.43-4.781.8960.03518.318392460444270.9970.04896.2
4.78-5.242.010.03518.988184422940720.9970.04796.3
5.24-5.862.1990.03918.098172382437170.9960.05297.2
5.86-6.762.190.03718.967215339332940.9960.0597.1
6.76-8.292.1880.02823.956050284327650.9980.03897.3
8.29-11.722.1630.01833.144650220621500.9990.02497.5
11.72-58.962.0640.01933.082357120511420.9990.02594.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UEL

6uel


Resolution: 2.62→58.96 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.921 / SU B: 15.054 / SU ML: 0.292 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.691 / ESU R Free: 0.316
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2503 5170 5 %RANDOM
Rwork0.1897 ---
obs0.1927 98950 96.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 205.89 Å2 / Biso mean: 60.404 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å2-0.02 Å20 Å2
2---0 Å20 Å2
3---0.04 Å2
Refinement stepCycle: final / Resolution: 2.62→58.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21554 0 66 136 21756
Biso mean--44.9 45.04 -
Num. residues----2786
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01922041
X-RAY DIFFRACTIONr_bond_other_d0.0020.0220759
X-RAY DIFFRACTIONr_angle_refined_deg1.5611.96729843
X-RAY DIFFRACTIONr_angle_other_deg0.9823.00148314
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.99852772
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.18125.021932
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.928153871
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.771598
X-RAY DIFFRACTIONr_chiral_restr0.0850.23402
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02124295
X-RAY DIFFRACTIONr_gen_planes_other0.0020.024175
LS refinement shellResolution: 2.62→2.688 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 381 -
Rwork0.347 7326 -
all-7707 -
obs--96.4 %

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