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

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Basic information

Entry
Database: PDB / ID: 3cdb
TitleThermodynamic and structure guided design of statin hmg-coa reductase inhibitors
Components3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA 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


ubiquinone metabolic process / hydroxymethylglutaryl-CoA reductase (NADPH) / negative regulation of striated muscle cell apoptotic process / hydroxymethylglutaryl-CoA reductase activity / hydroxymethylglutaryl-CoA reductase (NADPH) activity / negative regulation of amyloid-beta clearance / positive regulation of stress-activated MAPK cascade / sterol biosynthetic process / positive regulation of skeletal muscle tissue development / coenzyme A metabolic process ...ubiquinone metabolic process / hydroxymethylglutaryl-CoA reductase (NADPH) / negative regulation of striated muscle cell apoptotic process / hydroxymethylglutaryl-CoA reductase activity / hydroxymethylglutaryl-CoA reductase (NADPH) activity / negative regulation of amyloid-beta clearance / positive regulation of stress-activated MAPK cascade / sterol biosynthetic process / positive regulation of skeletal muscle tissue development / coenzyme A metabolic process / negative regulation of wound healing / negative regulation of insulin secretion involved in cellular response to glucose stimulus / isoprenoid biosynthetic process / peroxisomal membrane / myoblast differentiation / positive regulation of cardiac muscle cell apoptotic process / regulation of cholesterol biosynthetic process / coenzyme binding / cholesterol biosynthetic process / negative regulation of blood vessel diameter / negative regulation of protein secretion / visual learning / negative regulation of MAP kinase activity / protein phosphatase 2A binding / NADPH binding / response to nutrient / negative regulation of protein catabolic process / positive regulation of smooth muscle cell proliferation / protein tetramerization / regulation of lipid metabolic process / response to ethanol / positive regulation of ERK1 and ERK2 cascade / aging / endoplasmic reticulum membrane / endoplasmic reticulum / protein homodimerization activity / integral component of membrane
Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, class I/II / Sterol-sensing domain / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-coenzyme A reductase ...Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, class I/II / Sterol-sensing domain / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-coenzyme A reductase / HMGR, N-terminal domain / HMGR, N-terminal domain / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain / 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 / Alpha-Beta Plaits / Alpha-Beta Complex / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
3-hydroxy-3-methylglutaryl-coenzyme A reductase
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 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.
Validation Report
SummaryFull reportAbout validation report
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

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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)192,5418
Polymers189,9184
Non-polymers2,6234
Water11,403633
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25450 Å2
ΔGint-171 kcal/mol
Surface area55200 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)73.575, 173.484, 75.990
Angle α, β, γ (deg.)90.00, 118.68, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide
3-hydroxy-3-methylglutaryl-coenzyme A reductase / HMG-CoA 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-9HI / (3R,5R)-7-{3-[(4-carbamoylphenyl)sulfamoyl]-4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-pyrrol-1-yl}-3,5-dihydroxyheptanoic acid


Mass: 655.709 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H35F2N3O7S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 633 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 2.24 Å3/Da / Density % sol: 45.1 %
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: Jul 10, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 3.1 % / Av σ(I) over netI: 8.7 / Number: 211701 / Rmerge(I) obs: 0.063 / Χ2: 0.86 / D res high: 2.3 Å / D res low: 50 Å / Num. obs: 68943 / % possible obs: 92.8
Diffraction reflection shell

Diffraction-ID: 1

Highest resolution (Å)Lowest resolution (Å)% possible obs (%)Rmerge(I) obsChi squaredRedundancy
4.955098.40.030.8513.3
3.934.9599.20.0360.8813.3
3.443.9399.60.0460.8983.3
3.123.4499.70.0690.8783.3
2.93.1299.90.1020.8683.2
2.732.999.90.160.8393.2
2.592.7398.40.2090.8333.1
2.482.5990.10.2530.8352.9
2.382.4878.10.2820.8272.6
2.32.3864.40.3240.8222.3
ReflectionResolution: 2.3→50 Å / Num. obs: 68943 / % possible obs: 92.8 % / Redundancy: 3.1 % / Rmerge(I) obs: 0.063 / Χ2: 0.858 / Net I/σ(I): 8.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.3-2.382.30.32447810.82264.4
2.38-2.482.60.28257540.82778.1
2.48-2.592.90.25366550.83590.1
2.59-2.733.10.20973480.83398.4
2.73-2.93.20.1673730.83999.9
2.9-3.123.20.10274000.86899.9
3.12-3.443.30.06974230.87899.7
3.44-3.933.30.04674130.89899.6
3.93-4.953.30.03674010.88199.2
4.95-503.30.0373950.85198.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.004data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.915 / SU B: 8.074 / SU ML: 0.189 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.491 / ESU R Free: 0.257 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.239 3496 5.1 %RANDOM
Rwork0.202 ---
Obs0.204 68649 92.88 %-
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: 32.583 Å2
Baniso -1Baniso -2Baniso -3
1-0.8 Å20 Å2-1.18 Å2
2---1.29 Å20 Å2
3----0.64 Å2
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12292 0 184 633 13109
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0070.02112668
r_bond_other_d0.0020.0211714
r_angle_refined_deg1.1531.98617138
r_angle_other_deg0.887327282
r_dihedral_angle_1_deg5.44851647
r_chiral_restr0.0570.21960
r_gen_planes_refined0.0030.0214154
r_gen_planes_other0.0020.022368
r_nbd_refined0.1710.22726
r_nbd_other0.2060.213926
r_nbtor_other0.080.27608
r_xyhbond_nbd_refined0.1450.2651
r_symmetry_vdw_refined0.1560.219
r_symmetry_vdw_other0.1710.260
r_symmetry_hbond_refined0.1740.23
r_mcbond_it0.341.58170
r_mcangle_it0.648213062
r_scbond_it0.85234498
r_scangle_it1.5674.54076
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.347 175
Rwork0.271 3254
All-3429

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