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- PDB-2cw6: Crystal Structure of Human HMG-CoA Lyase: Insights into Catalysis... -

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Basic information

Entry
Database: PDB / ID: 2cw6
TitleCrystal Structure of Human HMG-CoA Lyase: Insights into Catalysis and the Molecular Basis for Hydroxymethylglutaric Aciduria
ComponentsHydroxymethylglutaryl-CoA lyase, mitochondrial
KeywordsLYASE / HMG-CoA Lyase / Ketogenic Enzyme
Function / homology
Function and homology information


hydroxymethylglutaryl-CoA lyase / hydroxymethylglutaryl-CoA lyase activity / ketone body biosynthetic process / Synthesis of Ketone Bodies / L-leucine catabolic process / peroxisomal matrix / mitochondrion organization / Peroxisomal protein import / lipid metabolic process / peroxisome ...hydroxymethylglutaryl-CoA lyase / hydroxymethylglutaryl-CoA lyase activity / ketone body biosynthetic process / Synthesis of Ketone Bodies / L-leucine catabolic process / peroxisomal matrix / mitochondrion organization / Peroxisomal protein import / lipid metabolic process / peroxisome / manganese ion binding / mitochondrial matrix / structural molecule activity / magnesium ion binding / protein-containing complex / mitochondrion / metal ion binding / cytosol
Similarity search - Function
Hydroxymethylglutaryl-CoA lyase, active site / Hydroxymethylglutaryl-coenzyme A lyase active site. / HMG-CoA lyase / Pyruvate carboxyltransferase / HMGL-like / Pyruvate carboxyltransferase domain. / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
3-HYDROXYPENTANEDIOIC ACID / Hydroxymethylglutaryl-CoA lyase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsFu, Z. / Runquist, J.A. / Hunt, J.F. / Miziorko, H.M. / Kim, J.-J.P.
CitationJournal: J.Biol.Chem. / Year: 2006
Title: Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria
Authors: Fu, Z. / Runquist, J.A. / Forouhar, F. / Hussain, M. / Hunt, J.F. / Miziorko, H.M. / Kim, J.-J.P.
History
DepositionJun 17, 2005Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 6, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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 / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hydroxymethylglutaryl-CoA lyase, mitochondrial
B: Hydroxymethylglutaryl-CoA lyase, mitochondrial
C: Hydroxymethylglutaryl-CoA lyase, mitochondrial
D: Hydroxymethylglutaryl-CoA lyase, mitochondrial
E: Hydroxymethylglutaryl-CoA lyase, mitochondrial
F: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)189,76013
Polymers189,4666
Non-polymers2947
Water10,178565
1
A: Hydroxymethylglutaryl-CoA lyase, mitochondrial
B: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3525
Polymers63,1552
Non-polymers1973
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2940 Å2
ΔGint-33 kcal/mol
Surface area22350 Å2
MethodPISA
2
C: Hydroxymethylglutaryl-CoA lyase, mitochondrial
D: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,2044
Polymers63,1552
Non-polymers492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint-33 kcal/mol
Surface area22260 Å2
MethodPISA
3
E: Hydroxymethylglutaryl-CoA lyase, mitochondrial
F: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,2044
Polymers63,1552
Non-polymers492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2490 Å2
ΔGint-34 kcal/mol
Surface area22630 Å2
MethodPISA
4
A: Hydroxymethylglutaryl-CoA lyase, mitochondrial
B: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules

A: Hydroxymethylglutaryl-CoA lyase, mitochondrial
B: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules

C: Hydroxymethylglutaryl-CoA lyase, mitochondrial
D: Hydroxymethylglutaryl-CoA lyase, mitochondrial
E: Hydroxymethylglutaryl-CoA lyase, mitochondrial
F: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules

C: Hydroxymethylglutaryl-CoA lyase, mitochondrial
D: Hydroxymethylglutaryl-CoA lyase, mitochondrial
E: Hydroxymethylglutaryl-CoA lyase, mitochondrial
F: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)379,51926
Polymers378,93212
Non-polymers58814
Water21612
TypeNameSymmetry operationNumber
crystal symmetry operation3_455x-1/2,y+1/2,z1
crystal symmetry operation4_556-x+1/2,y+1/2,-z+11
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area27140 Å2
ΔGint-221 kcal/mol
Surface area123110 Å2
MethodPISA
5
A: Hydroxymethylglutaryl-CoA lyase, mitochondrial
B: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules

C: Hydroxymethylglutaryl-CoA lyase, mitochondrial
D: Hydroxymethylglutaryl-CoA lyase, mitochondrial
E: Hydroxymethylglutaryl-CoA lyase, mitochondrial
F: Hydroxymethylglutaryl-CoA lyase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)189,76013
Polymers189,4666
Non-polymers2947
Water1086
TypeNameSymmetry operationNumber
crystal symmetry operation3_455x-1/2,y+1/2,z1
identity operation1_555x,y,z1
Buried area10480 Å2
ΔGint-103 kcal/mol
Surface area64650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)196.990, 117.080, 86.830
Angle α, β, γ (deg.)90.00, 112.50, 90.00
Int Tables number5
Space group name H-MC121
DetailsBiological unit is Dimer. dimer is consisted of monomer A and B or C and D or E and F

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Components

#1: Protein
Hydroxymethylglutaryl-CoA lyase, mitochondrial / HMG-CoA lyase / HL / 3-hydroxy-3-methylglutarate-CoA lyase


Mass: 31577.627 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTrc99a, pTrc-HL1 / Production host: Escherichia coli (E. coli) / Strain (production host): JM105
References: UniProt: P35914, hydroxymethylglutaryl-CoA lyase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-3HG / 3-HYDROXYPENTANEDIOIC ACID / 3-HYDROXYGLUTARIC ACID


Mass: 148.114 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H8O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 565 / Source method: isolated from a natural source / Formula: H2O

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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: 2.2 Å3/Da / Density % sol: 49.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: PEG8000, HEPEG8000, HEPES buffer, MgCl2, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 3, 2004
RadiationMonochromator: Ge 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→30.44 Å / Num. obs: 103975 / % possible obs: 98.2 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 2 / Redundancy: 5.4 % / Biso Wilson estimate: 15.5 Å2 / Rsym value: 0.074 / Net I/σ(I): 11.8
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 3.9 % / Mean I/σ(I) obs: 2.1 / Num. unique all: 5129 / Rsym value: 0.278

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→30.44 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 527927.32 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.265 10457 10.1 %RANDOM
Rwork0.226 ---
obs0.226 103975 98.2 %-
all-103975 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.5413 Å2 / ksol: 0.344664 e/Å3
Displacement parametersBiso mean: 45.9 Å2
Baniso -1Baniso -2Baniso -3
1-3.9 Å20 Å27.93 Å2
2--0.77 Å20 Å2
3----4.67 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.34 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.38 Å0.35 Å
Refinement stepCycle: LAST / Resolution: 2.1→30.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12962 0 16 565 13543
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.4
X-RAY DIFFRACTIONc_improper_angle_d0.96
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.008 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.346 1683 10.1 %
Rwork0.328 15017 -
obs--94.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4hgc.parhgc.top

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