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

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Basic information

Entry
Database: PDB / ID: 1hwl
TitleCOMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ROSUVASTATIN (FORMALLY KNOWN AS ZD4522)
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 / sterol biosynthetic process / coenzyme A binding / negative regulation of amyloid-beta clearance / coenzyme A metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / peroxisomal membrane ...hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / GTPase regulator activity / sterol biosynthetic process / coenzyme A binding / negative regulation of amyloid-beta clearance / coenzyme A metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / 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 / negative regulation of protein catabolic process / PPARA activates gene expression / 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 / Chem-FBI / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / difference fourier / Resolution: 2.1 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: 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

Downloads & links

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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)203,30211
Polymers200,0864
Non-polymers3,2167
Water3,279182
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area28550 Å2
ΔGint-183 kcal/mol
Surface area49710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.432, 172.512, 79.987
Angle α, β, γ (deg.)90.00, 117.36, 90.00
Int Tables number4
Cell settingmonoclinic
Space group name H-MP1211

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Components

#1: Protein
HMG-COA REDUCTASE / / 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
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 / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-FBI / 7-[4-(4-FLUORO-PHENYL)-6-ISOPROPYL-2-(METHANESULFONYL-METHYL-AMINO)-PYRIMIDIN-5-YL] -3,5-DIHYDROXY-HEPTANOIC ACID / ROSUVASTATIN / Rosuvastatin


Mass: 483.554 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H30FN3O6S / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 2

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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, microseeding
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

Diffraction
IDMean temperature (K)Crystal-ID
11301
21231
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONALS 5.0.111.1
SYNCHROTRONCHESS F120.942
Detector
TypeIDDetectorDateDetails
ADSC QUANTUM 41CCDMay 4, 2000
ADSC QUANTUM 42CCDJul 2, 2000mirror
RadiationMonochromator: horizontally bent Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.11
20.9421
ReflectionResolution: 2.1→100 Å / Num. all: 101858 / Num. obs: 101858 / % possible obs: 97.6 % / Observed criterion σ(I): -3 / Redundancy: 5 % / Biso Wilson estimate: 27.1 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 21.1
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 2 % / Rmerge(I) obs: 0.473 / Mean I/σ(I) obs: 1.3 / Num. unique all: 4532 / % possible all: 87.6
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
Resolution: 2.1→43.29 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 2376841.76 / 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
Rfree0.239 2006 2 %RANDOM
Rwork0.219 ---
all-101733 --
obs-101733 97.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 32.16 Å2 / ksol: 0.353 e/Å3
Displacement parametersBiso mean: 55.4 Å2
Baniso -1Baniso -2Baniso -3
1-1.33 Å20 Å213.25 Å2
2---4.08 Å20 Å2
3---2.75 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.31 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.33 Å0.35 Å
Refinement stepCycle: LAST / Resolution: 2.1→43.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11764 0 213 182 12159
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.087
X-RAY DIFFRACTIONc_angle_deg1.7
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d1.35
X-RAY DIFFRACTIONc_mcbond_it0.71.5
X-RAY DIFFRACTIONc_mcangle_it1.212
X-RAY DIFFRACTIONc_scbond_it1.072
X-RAY DIFFRACTIONc_scangle_it1.652.5
Refine LS restraints NCSWeight Biso : 5 / Weight position: 250
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.017 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.314 329 2.1 %
Rwork0.329 15422 -
obs--91 %
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 DIFFRACTION5FBI_PAR:FBI.PARAMFBI_PAR:FBI.TOP
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
% reflection Rfree: 2 % / Rfactor obs: 0.219
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 55.4 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.7
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.1
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.35
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: 0.314 / % reflection Rfree: 2.1 % / Rfactor Rwork: 0.329

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