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- PDB-2p8u: Crystal structure of human 3-hydroxy-3-methylglutaryl CoA synthase I -

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Basic information

Entry
Database: PDB / ID: 2p8u
TitleCrystal structure of human 3-hydroxy-3-methylglutaryl CoA synthase I
ComponentsHydroxymethylglutaryl-CoA synthase, cytoplasmic
KeywordsTRANSFERASE / hydromethylglutaryl CoA / mevalonate pathway / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / lipid metabolic process / protein homodimerization activity ...farnesyl diphosphate biosynthetic process, mevalonate pathway / hydroxymethylglutaryl-CoA synthase / hydroxymethylglutaryl-CoA synthase activity / Cholesterol biosynthesis / acetyl-CoA metabolic process / cholesterol biosynthetic process / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / lipid metabolic process / protein homodimerization activity / cytosol / cytoplasm
Similarity search - Function
Hydroxymethylglutaryl-coenzyme A synthase, active site / Hydroxymethylglutaryl-CoA synthase, eukaryotic / Hydroxymethylglutaryl-coenzyme A synthase active site. / Hydroxymethylglutaryl-coenzyme A synthase, N-terminal / Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain / Hydroxymethylglutaryl-coenzyme A synthase N terminal / Hydroxymethylglutaryl-coenzyme A synthase C terminal / Thiolase/Chalcone synthase / Peroxisomal Thiolase; Chain A, domain 1 / Thiolase-like ...Hydroxymethylglutaryl-coenzyme A synthase, active site / Hydroxymethylglutaryl-CoA synthase, eukaryotic / Hydroxymethylglutaryl-coenzyme A synthase active site. / Hydroxymethylglutaryl-coenzyme A synthase, N-terminal / Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain / Hydroxymethylglutaryl-coenzyme A synthase N terminal / Hydroxymethylglutaryl-coenzyme A synthase C terminal / Thiolase/Chalcone synthase / Peroxisomal Thiolase; Chain A, domain 1 / Thiolase-like / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
COENZYME A / Hydroxymethylglutaryl-CoA synthase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsTurnbull, A. / Shafqat, N. / Salah, E. / Niesen, F.H. / Burgess, N. / Bunkoczi, G. / Debreczeni, J. / Pike, A.C.W. / Umeano, C. / Gorrec, F. ...Turnbull, A. / Shafqat, N. / Salah, E. / Niesen, F.H. / Burgess, N. / Bunkoczi, G. / Debreczeni, J. / Pike, A.C.W. / Umeano, C. / Gorrec, F. / von Delft, F. / Weigelt, J. / Arrowsmith, C.H. / Sundstrom, M. / Edwards, A. / Oppermann, U. / Structural Genomics Consortium (SGC)
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design.
Authors: Shafqat, N. / Turnbull, A. / Zschocke, J. / Oppermann, U. / Yue, W.W.
History
DepositionMar 23, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Aug 30, 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 / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_auth_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_auth_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
B: Hydroxymethylglutaryl-CoA synthase, cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,2935
Polymers106,6662
Non-polymers1,6273
Water13,421745
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8460 Å2
ΔGint-19 kcal/mol
Surface area31610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.762, 92.762, 235.532
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31A
41B
51A
61B
71A
81B
91A
101B
111A
121B
131A
141B

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11TYRTYRHISHIS2AA11 - 24119 - 249
21TYRTYRHISHIS2BB11 - 24119 - 249
32ALAALAPHEPHE5AA242 - 253250 - 261
42ALAALAPHEPHE5BB242 - 253250 - 261
53THRTHRASNASN2AA254 - 285262 - 293
63THRTHRASNASN2BB254 - 285262 - 293
74ASPASPILEILE5AA286 - 294294 - 302
84ASPASPILEILE5BB286 - 294294 - 302
95TYRTYRVALVAL2AA295 - 388303 - 396
105TYRTYRVALVAL2BB295 - 388303 - 396
116THRTHRILEILE5AA389 - 401397 - 409
126THRTHRILEILE5BB389 - 401397 - 409
137THRTHRPROPRO2AA402 - 470410 - 478
147THRTHRPROPRO2BB402 - 470410 - 478

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Components

#1: Protein Hydroxymethylglutaryl-CoA synthase, cytoplasmic / HMG-CoA synthase / 3-hydroxy-3-methylglutaryl coenzyme A synthase


Mass: 53332.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HMGCS1, HMGCS / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3/Rosetta
References: UniProt: Q01581, hydroxymethylglutaryl-CoA synthase
#2: Chemical ChemComp-COA / COENZYME A


Mass: 767.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H36N7O16P3S
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 745 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.37 Å3/Da / Density % sol: 48.2 %
Crystal growTemperature: 297 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2M (NH4)2SO4, 0.1M Bis-Tris pH 6.5, 25% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99999 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 16, 2006
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 66668 / Num. obs: 66668 / % possible obs: 94.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5 % / Rmerge(I) obs: 0.128
Reflection shellResolution: 2→2.07 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.722 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MAR345CCDdata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 2FA0,2F82,2FA3,2F9A,1XPL

2fa0

2f82

2fa3

2f9a

1xpl


Resolution: 2→50 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.95 / SU B: 6.328 / SU ML: 0.095 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.168 / ESU R Free: 0.149 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20227 3380 5.1 %RANDOM
Rwork0.15933 ---
all0.16149 63108 --
obs0.16149 63108 94.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.337 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å20 Å20 Å2
2--0.22 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7135 0 102 745 7982
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0227399
X-RAY DIFFRACTIONr_bond_other_d0.0020.024861
X-RAY DIFFRACTIONr_angle_refined_deg1.3451.97110045
X-RAY DIFFRACTIONr_angle_other_deg1.3783.00211775
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.025930
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.21224.481337
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.14151195
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0881538
X-RAY DIFFRACTIONr_chiral_restr0.0820.21113
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.028340
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021516
X-RAY DIFFRACTIONr_nbd_refined0.2050.21503
X-RAY DIFFRACTIONr_nbd_other0.1920.25174
X-RAY DIFFRACTIONr_nbtor_refined0.1770.23621
X-RAY DIFFRACTIONr_nbtor_other0.0930.23598
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2638
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1720.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2270.220
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1540.221
X-RAY DIFFRACTIONr_mcbond_it2.5234708
X-RAY DIFFRACTIONr_mcbond_other0.65431906
X-RAY DIFFRACTIONr_mcangle_it3.46357337
X-RAY DIFFRACTIONr_scbond_it5.8783099
X-RAY DIFFRACTIONr_scangle_it7.182112704
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
2502tight positional0.050.05
3181medium positional0.340.5
208loose positional0.485
2502tight thermal0.410.5
3181medium thermal1.122
208loose thermal3.0310
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 257 -
Rwork0.192 4847 -
obs--99.67 %
Refinement TLS params.

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

IDL11 (°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)
10.7117-0.0410.1090.7851-0.07451.1780.00550.01370.0676-0.01630.02380.0943-0.0866-0.1747-0.0293-0.0850.0097-0.0155-0.0713-0.0096-0.085220.326327.495363.9642
20.68260.00870.22520.6309-0.09731.3024-0.00280.0024-0.03330.0218-0.0042-0.0890.03380.14260.007-0.0860.0047-0.0187-0.0932-0.0014-0.103146.723124.040484.0571
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A46 - 470
2X-RAY DIFFRACTION2B46 - 470

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