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- PDB-3cda: Thermodynamic and structure guided design of statin hmg-coa reduc... -

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Basic information

Entry
Database: PDB / ID: 3cda
TitleThermodynamic and structure guided design of statin hmg-coa reductase inhibitors
Components3-hydroxy-3-methylglutaryl-coenzyme A reductase
KeywordsOXIDOREDUCTASE / CHOLESTEROL BIOSYNTHESIS / HMG-COA / NADPH / STATIN / Alternative splicing / Endoplasmic reticulum / Glycoprotein / Lipid synthesis / Membrane / Peroxisome / Polymorphism / Steroid biosynthesis / Transmembrane
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 / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / 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 / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / isoprenoid biosynthetic process / peroxisomal membrane / 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 / PPARA activates gene expression / visual learning / 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 / 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-8HI / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.07 Å
AuthorsPavlovsky, A. / Sarver, R.W. / Harris, M.S. / Finzel, B.C.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme a reductase.
Authors: Sarver, R.W. / Bills, E. / Bolton, G. / Bratton, L.D. / Caspers, N.L. / Dunbar, J.B. / Harris, M.S. / Hutchings, R.H. / Kennedy, R.M. / Larsen, S.D. / Pavlovsky, A. / Pfefferkorn, J.A. / Bainbridge, G.
History
DepositionFeb 26, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Oct 20, 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 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
B: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
C: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
D: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,4698
Polymers189,9184
Non-polymers2,5514
Water8,881493
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25520 Å2
ΔGint-175.4 kcal/mol
Surface area54900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.611, 172.249, 75.620
Angle α, β, γ (deg.)90.000, 118.040, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
3-hydroxy-3-methylglutaryl-coenzyme A reductase / HMG-CoA reductase


Mass: 47479.551 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN (RESIDUES 441-875) / Mutation: M485I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HMGCR / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 STAR
References: UniProt: P04035, hydroxymethylglutaryl-CoA reductase (NADPH)
#2: Chemical
ChemComp-8HI / (3R,5R)-7-{3-(4-fluorophenyl)-1-(1-methylethyl)-4-phenyl-5-[(4-sulfamoylphenyl)carbamoyl]-1H-pyrrol-2-yl}-3,5-dihydroxyheptanoic acid


Mass: 637.718 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H36FN3O7S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 493 / 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: 44.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: protein 15-20 mg/ml, Ligand (saturated),PEG 4000, MgCl2 0.2M, Tris-HCL pH8 0.1M, 7-10 days, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 19, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionAv σ(I) over netI: 13 / Number: 289244 / Rmerge(I) obs: 0.066 / Χ2: 0.95 / D res high: 2.08 Å / D res low: 50 Å / Num. obs: 90237 / % possible obs: 90.7
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squared
4.48509510.0510.922
3.564.4892.210.0510.882
3.113.5693.510.0640.914
2.823.1194.910.0821.075
2.622.8295.810.1040.934
2.472.6295.410.1280.963
2.342.4791.810.141.03
2.242.3486.910.1550.915
2.152.2483.810.1750.986
2.082.1578.210.1990.887
ReflectionResolution: 2.07→50 Å / Num. obs: 90237 / % possible obs: 90.7 % / Rmerge(I) obs: 0.066 / Χ2: 0.952 / Net I/σ(I): 13
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
2.08-2.150.19977360.88778.2
2.15-2.240.17583170.98683.8
2.24-2.340.15586080.91586.9
2.34-2.470.1491121.0391.8
2.47-2.620.12894910.96395.4
2.62-2.820.10495170.93495.8
2.82-3.110.08293961.07594.9
3.11-3.560.06493030.91493.5
3.56-4.480.05192240.88292.2
4.48-500.05195330.92295

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.004data extraction
RefinementResolution: 2.07→50 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.923 / SU B: 6.301 / SU ML: 0.167 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.274 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.257 2066 2.3 %RANDOM
Rwork0.213 ---
obs0.214 90191 90.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 34.538 Å2
Baniso -1Baniso -2Baniso -3
1-2.18 Å20 Å2-2.89 Å2
2---3.21 Å20 Å2
3----1.69 Å2
Refinement stepCycle: LAST / Resolution: 2.07→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12298 0 180 493 12971
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.02112669
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211729
X-RAY DIFFRACTIONr_angle_refined_deg1.1961.98717140
X-RAY DIFFRACTIONr_angle_other_deg0.747327316
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.66951650
X-RAY DIFFRACTIONr_chiral_restr0.060.21965
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0214159
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022363
X-RAY DIFFRACTIONr_nbd_refined0.1840.22795
X-RAY DIFFRACTIONr_nbd_other0.2160.214213
X-RAY DIFFRACTIONr_nbtor_other0.080.27719
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2551
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1610.219
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1970.274
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1650.29
X-RAY DIFFRACTIONr_mcbond_it0.3991.58211
X-RAY DIFFRACTIONr_mcangle_it0.752213121
X-RAY DIFFRACTIONr_scbond_it1.02334458
X-RAY DIFFRACTIONr_scangle_it1.7564.54019
LS refinement shellResolution: 2.068→2.122 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.351 137
Rwork0.272 5298
all-5435

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