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- PDB-6uel: CPS1 bound to allosteric inhibitor H3B-193 -

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Basic information

Entry
Database: PDB / ID: 6uel
TitleCPS1 bound to allosteric inhibitor H3B-193
ComponentsCarbamoyl-phosphate synthase [ammonia], mitochondrial
KeywordsLIGASE/LIGASE INHIBITOR / allosteric inhibitor / CPS1 / ligase / TRANSFERASE / LIGASE-LIGASE 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 / homocysteine metabolic process / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / nitric oxide metabolic process ...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 / homocysteine metabolic process / carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity / nitric oxide 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 / response to zinc ion / response to dexamethasone / response to starvation / glutamine metabolic process / mitochondrial nucleoid / cellular response to glucagon stimulus / response to amine / potassium ion binding / small molecule binding / 'de novo' pyrimidine nucleobase biosynthetic process / response to amino acid / cellular response to cAMP / phospholipid binding / response to toxic substance / vasodilation / endopeptidase activity / mitochondrial inner membrane / response to lipopolysaccharide / 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-Q5A / Carbamoyl-phosphate synthase [ammonia], mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLarsen, N.A. / Nguyen, T.V.
CitationJournal: 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
DepositionSep 21, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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)331,1696
Polymers330,2572
Non-polymers9124
Water29,2201622
1
A: Carbamoyl-phosphate synthase [ammonia], mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,5843
Polymers165,1291
Non-polymers4562
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)165,5843
Polymers165,1291
Non-polymers4562
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.587, 132.342, 142.443
Angle α, β, γ (deg.)90.000, 102.570, 90.000
Int Tables number4
Space group name H-MP1211

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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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-Q5A / N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide


Mass: 390.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23FN4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1622 / 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: 3.12 Å3/Da / Density % sol: 60.56 %
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: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 20, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→139.03 Å / Num. obs: 281085 / % possible obs: 99.3 % / Redundancy: 5 % / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.048 / Rrim(I) all: 0.11 / Χ2: 0.885 / Net I/σ(I): 6.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.934.80.987140090.6110.4991.110.98299.7
1.93-1.974.70.756140770.7480.3850.8520.70199.5
1.97-2.014.90.637140770.8160.3150.7130.66899.7
2.01-2.055.10.533140290.8720.2590.5950.6999.6
2.05-2.0950.508140300.8520.2490.5670.92299.5
2.09-2.1450.384140260.9160.1890.4290.73799.6
2.14-2.194.90.331140640.9280.1650.3710.75499.4
2.19-2.254.70.322140100.9160.1630.3621.10899.4
2.25-2.325.10.269141460.9560.1310.30.87399.6
2.32-2.394.80.203140080.9650.1020.2280.80899.6
2.39-2.485.10.182140840.9720.0880.2030.81399.7
2.48-2.585.10.154140970.9770.0740.1720.8499.7
2.58-2.75.10.137140760.9770.0660.1530.93899.5
2.7-2.844.90.112139980.9820.0560.1250.9499.1
2.84-3.025.10.098140840.9840.0470.1090.98499.5
3.02-3.2550.081140740.9850.040.0911.03699.4
3.25-3.585.20.071140930.9880.0340.0791.09799.3
3.58-4.094.90.062139510.9890.0310.071.11298.4
4.09-5.1650.055140960.990.0270.0610.95598.9
5.16-505.10.05140560.9930.0240.0550.74397.5

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5DOT

5dot


Resolution: 1.9→139.03 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.94 / SU B: 3.28 / SU ML: 0.092 / SU R Cruickshank DPI: 0.1173 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.117 / ESU R Free: 0.116
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2086 14084 5 %RANDOM
Rwork0.172 ---
obs0.1739 268563 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 134.11 Å2 / Biso mean: 30.467 Å2 / Biso min: 11.21 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å2-0 Å2-0 Å2
2--0 Å20 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 1.9→139.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20622 0 56 1623 22301
Biso mean--24.78 34.27 -
Num. residues----2665
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.01921077
X-RAY DIFFRACTIONr_bond_other_d0.0020.0219873
X-RAY DIFFRACTIONr_angle_refined_deg1.8411.96828543
X-RAY DIFFRACTIONr_angle_other_deg1.0673.00146247
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.65652650
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.34925.034892
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.664153701
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0051595
X-RAY DIFFRACTIONr_chiral_restr0.1190.23261
X-RAY DIFFRACTIONr_gen_planes_refined0.010.02123228
X-RAY DIFFRACTIONr_gen_planes_other0.0020.023987
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.316 1063 -
Rwork0.309 19854 -
obs--99.81 %

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