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

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Basic information

Entry
Database: PDB / ID: 3cct
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 / 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
Chem-3HI / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.12 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
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
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)192,2178
Polymers189,9184
Non-polymers2,2994
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25100 Å2
ΔGint-171.8 kcal/mol
Surface area54820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.940, 173.510, 76.400
Angle α, β, γ (deg.)90.000, 119.180, 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-3HI / (3R,5R)-7-[2-(4-fluorophenyl)-4-[(2-hydroxyphenyl)carbamoyl]-5-(1-methylethyl)-3-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid


Mass: 574.639 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H35FN2O6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.25 Å3/Da / Density % sol: 45.41 %
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-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Apr 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: 11.8 / Number: 193726 / Rmerge(I) obs: 0.085 / Χ2: 1.23 / D res high: 2.1 Å / D res low: 30 Å / Num. obs: 86863 / % possible obs: 88.6
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squared
4.52308810.0621.301
3.594.5291.510.081.069
3.143.5992.810.0911.153
2.853.1494.210.1011.105
2.652.8594.810.1171.191
2.492.6595.210.1341.211
2.372.4995.710.1571.348
2.262.3795.610.1831.195
2.182.2692.910.2321.531
2.12.1845.210.2481.167
ReflectionResolution: 2.1→30 Å / Num. obs: 86863 / % possible obs: 88.6 % / Rmerge(I) obs: 0.085 / Χ2: 1.228 / Net I/σ(I): 11.8
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
2.1-2.180.24844201.16745.2
2.18-2.260.23291021.53192.9
2.26-2.370.18393151.19595.6
2.37-2.490.15793831.34895.7
2.49-2.650.13493421.21195.2
2.65-2.850.11792791.19194.8
2.85-3.140.10191771.10594.2
3.14-3.590.09191171.15392.8
3.59-4.520.0890081.06991.5
4.52-300.06287201.30188

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.004data extraction
ADSCQuantumdata collection
HKL-2000data reduction
RefinementResolution: 2.12→30 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.93 / SU B: 6.056 / SU ML: 0.156 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.325 / ESU R Free: 0.222 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.236 8471 10.1 %RANDOM
Rwork0.196 ---
obs0.2 84267 88.69 %-
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: 35.169 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20 Å20.57 Å2
2---0.54 Å20 Å2
3----0.26 Å2
Refinement stepCycle: LAST / Resolution: 2.12→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12282 0 168 395 12845
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02112642
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211703
X-RAY DIFFRACTIONr_angle_refined_deg1.2511.98617095
X-RAY DIFFRACTIONr_angle_other_deg0.771327258
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.39151648
X-RAY DIFFRACTIONr_chiral_restr0.0640.21957
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214137
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022357
X-RAY DIFFRACTIONr_nbd_refined0.1960.22762
X-RAY DIFFRACTIONr_nbd_other0.2270.213966
X-RAY DIFFRACTIONr_nbtor_other0.0810.27501
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1470.2469
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.120.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1910.261
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.190.23
X-RAY DIFFRACTIONr_mcbond_it0.571.58174
X-RAY DIFFRACTIONr_mcangle_it1.097213065
X-RAY DIFFRACTIONr_scbond_it1.52734468
X-RAY DIFFRACTIONr_scangle_it2.6974.54030
LS refinement shellResolution: 2.119→2.174 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.314 447
Rwork0.277 3935
all-4382

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