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- PDB-1hw9: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ... -

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Basic information

Entry
Database: PDB / ID: 1hw9
TitleCOMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH SIMVASTATIN
ComponentsHMG-COA REDUCTASE
KeywordsOXIDOREDUCTASE / protein-inhibitor complex
Function / homology
Function and homology information


hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / sterol biosynthetic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / peroxisomal membrane ...hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / sterol biosynthetic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / peroxisomal membrane / isoprenoid biosynthetic process / cholesterol biosynthetic process / negative regulation of protein secretion / NADPH binding / regulation of ERK1 and ERK2 cascade / Activation of gene expression by SREBF (SREBP) / long-term synaptic potentiation / visual learning / PPARA activates gene expression / negative regulation of protein catabolic process / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
HMGR, N-terminal domain / HMGR, N-terminal domain / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-coenzyme A reductases signature 1. ...HMGR, N-terminal domain / HMGR, N-terminal domain / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-coenzyme A reductases signature 1. / Hydroxymethylglutaryl-coenzyme A reductases signature 3. / Hydroxymethylglutaryl-CoA reductase, class I/II / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-coenzyme A reductase / Hydroxymethylglutaryl-coenzyme A reductases family profile. / : / Sterol-sensing domain of SREBP cleavage-activation / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / Alpha-Beta Plaits / Alpha-Beta Complex / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Simvastatin acid / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / difference fourier / Resolution: 2.33 Å
AuthorsIstvan, E.S. / Deisenhofer, J.
CitationJournal: Science / Year: 2001
Title: Structural mechanism for statin inhibition of HMG-CoA reductase.
Authors: Istvan, E.S. / Deisenhofer, J.
History
DepositionJan 9, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2001Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Category: database_2 / 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 9, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HMG-COA REDUCTASE
B: HMG-COA REDUCTASE
C: HMG-COA REDUCTASE
D: HMG-COA REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,96813
Polymers200,0864
Non-polymers3,8829
Water3,171176
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area29940 Å2
ΔGint-198 kcal/mol
Surface area49290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.550, 172.817, 80.033
Angle α, β, γ (deg.)90.00, 117.56, 90.00
Int Tables number4
Cell settingmonoclinic
Space group name H-MP1211

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Components

#1: Protein
HMG-COA REDUCTASE / E.C.1.1.1.34 / 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE / HYDROXYMETHYLGLUTARYL-COA REDUCTASE


Mass: 50021.523 Da / Num. of mol.: 4 / Fragment: CATALYTIC PORTION / Mutation: M485I
Source method: isolated from a genetically manipulated source
Details: COMPLEXED WITH CHEMICALLY MODIFIED COMPACTIN (MEVASTATIN), NATURAL PRODUCT OF PENICILLIUM CITRINUM
Source: (gene. exp.) Homo sapiens (human) / Gene: HMGCR / Plasmid: PGEX-CS / Production host: Escherichia coli (E. coli) / Strain (production host): DH5ALPHA
References: UniProt: P04035, hydroxymethylglutaryl-CoA reductase (NADPH)
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-SIM / Simvastatin acid / DIMETHYL-COMPACTIN


Mass: 436.582 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H40O6 / Comment: medication*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.3 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 294 K / Method: microseeding / pH: 7.5
Details: PEG 4000, ammonium acetate, glycerol, DTT, Hepes, Microseeding, pH 7.5 at 294 K
Crystal grow
*PLUS
Temperature: 21 ℃ / Method: batch method / Details: used microseeding
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
13-5 mg/mlprotein11
212-15 %(w/v)PEG400011
30.15-0.2 Mammonium acetate11
425 mMsodium HEPES11
550 mMdithiothreitol11
610 mMADP11
710 %glycerol11

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Data collection

DiffractionMean temperature: 123 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: F1 / Wavelength: 0.942 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 2, 2000 / Details: mirror
RadiationMonochromator: horizontally bent Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.942 Å / Relative weight: 1
ReflectionResolution: 2.33→100 Å / Num. all: 73854 / Num. obs: 73854 / % possible obs: 95.8 % / Observed criterion σ(I): -3 / Redundancy: 3.9 % / Biso Wilson estimate: 41.4 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 20.7
Reflection shellResolution: 2.33→2.37 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.452 / Mean I/σ(I) obs: 1.6 / Num. unique all: 2376 / % possible all: 61.7
Reflection
*PLUS

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: difference fourier
Starting model: pdb entry 1dqa

1dqa


Resolution: 2.33→43.43 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 2255361.55 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(I): -3 / Stereochemistry target values: Engh & Huber / Details: ncs-restraints were used
RfactorNum. reflection% reflectionSelection details
Rfree0.248 2000 2.7 %RANDOM
Rwork0.222 ---
all-73699 --
obs-73699 96.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 33.72 Å2 / ksol: 0.345 e/Å3
Displacement parametersBiso mean: 60.4 Å2
Baniso -1Baniso -2Baniso -3
1-9.61 Å20 Å218.65 Å2
2---13.88 Å20 Å2
3---4.27 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.31 Å
Luzzati d res low-5 Å
Luzzati sigma a0.45 Å0.37 Å
Refinement stepCycle: LAST / Resolution: 2.33→43.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11750 0 259 176 12185
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d1.31
X-RAY DIFFRACTIONc_mcbond_it0.71.5
X-RAY DIFFRACTIONc_mcangle_it1.242
X-RAY DIFFRACTIONc_scbond_it0.982
X-RAY DIFFRACTIONc_scangle_it1.52.5
Refine LS restraints NCSWeight Biso : 5 / Weight position: 250
LS refinement shellResolution: 2.33→2.48 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.354 290 2.6 %
Rwork0.318 10857 -
obs--87.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4ADP_PAR:ADP.PARAMADP_PAR:ADP.TOP
X-RAY DIFFRACTION5SIM_PAR:SIM.PARAMSIM_PAR:SIM.TOP
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
% reflection Rfree: 2.7 % / Rfactor obs: 0.222
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 60.4 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.1
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.31
X-RAY DIFFRACTIONc_mcbond_it1.5
X-RAY DIFFRACTIONc_scbond_it2
X-RAY DIFFRACTIONc_mcangle_it2
X-RAY DIFFRACTIONc_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.354 / % reflection Rfree: 2.6 % / Rfactor Rwork: 0.318

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