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

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Basic information

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


hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / sterol biosynthetic process / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / Cholesterol biosynthesis / coenzyme A metabolic process / EGR2 and SOX10-mediated initiation of Schwann cell myelination / isoprenoid biosynthetic process ...hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / sterol biosynthetic process / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / Cholesterol biosynthesis / coenzyme A metabolic process / EGR2 and SOX10-mediated initiation of Schwann cell myelination / isoprenoid biosynthetic process / peroxisomal membrane / cholesterol biosynthetic process / negative regulation of protein secretion / regulation of ERK1 and ERK2 cascade / NADPH binding / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / negative regulation of protein catabolic process / visual learning / long-term synaptic potentiation / 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 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain / 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 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain / 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
Chem-116 / ADENOSINE-5'-DIPHOSPHATE / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / difference fourier / Resolution: 2.26 Å
AuthorsIstvan, E.S. / Deisenhofer, J.
CitationJournal: Science / Year: 2001
Title: Structural mechanism for statin inhibition of HMG-CoA reductase.
Authors: E S Istvan / J Deisenhofer /
Abstract: HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar ...HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
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)204,49614
Polymers200,0864
Non-polymers4,40910
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area31090 Å2
ΔGint-213 kcal/mol
Surface area50930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.616, 172.983, 80.159
Angle α, β, γ (deg.)90.00, 117.35, 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
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.: 6 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-116 / 7-[4-(4-FLUORO-PHENYL)-5-HYDROXYMETHYL-2,6-DIISOPROPYL-PYRIDIN-3-YL]-3,5-DIHYDROXY-HEPTANOIC ACID / CERIVASTATIN


Mass: 461.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H36FNO5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / 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, 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

DiffractionMean temperature: 123 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: F1 / Wavelength: 0.942 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 30, 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: 2.26→100 Å / Num. all: 80912 / Num. obs: 80912 / % possible obs: 96 % / Observed criterion σ(I): -3 / Redundancy: 4 % / Biso Wilson estimate: 33 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 28.7
Reflection shellResolution: 2.26→2.29 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.514 / Num. unique all: 3302 / % possible all: 78.2
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: 2.26→43.5 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 2264580.47 / 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
Rfree0.237 2029 2.5 %RANDOM
Rwork0.221 ---
all-80409 --
obs-80409 96 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 27.87 Å2 / ksol: 0.331 e/Å3
Displacement parametersBiso mean: 55.1 Å2
Baniso -1Baniso -2Baniso -3
1-1.11 Å20 Å212.55 Å2
2---3.52 Å20 Å2
3---2.41 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.31 Å
Luzzati d res low-5 Å
Luzzati sigma a0.38 Å0.4 Å
Refinement stepCycle: LAST / Resolution: 2.26→43.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11938 0 294 186 12418
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_improper_angle_d1.39
X-RAY DIFFRACTIONc_mcbond_it0.831.5
X-RAY DIFFRACTIONc_mcangle_it1.442
X-RAY DIFFRACTIONc_scbond_it1.242
X-RAY DIFFRACTIONc_scangle_it1.882.5
Refine LS restraints NCSWeight Biso : 5 / Weight position: 250
LS refinement shellResolution: 2.25→2.39 Å / Rfactor Rfree error: 0.025 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.403 269 2.5 %
Rwork0.366 10569 -
obs--76.6 %
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 DIFFRACTION5CER_PAR:CER.PARAMCER_PAR:CER.TOP
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
% reflection Rfree: 2.5 % / Rfactor obs: 0.221
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 55.1 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.9
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.39
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: 0.403 / % reflection Rfree: 2.5 % / Rfactor Rwork: 0.366

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