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- PDB-3cd5: Thermodynamic and structure guided design of statin hmg-coa reduc... -

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Basic information

Entry
Database: PDB / ID: 3cd5
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 / 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-7HI / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.39 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)192,37712
Polymers189,9184
Non-polymers2,4598
Water8,035446
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26820 Å2
ΔGint-246.3 kcal/mol
Surface area55100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.041, 173.178, 75.962
Angle α, β, γ (deg.)90.000, 118.760, 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-7HI / (3R,5R)-7-[3-(biphenyl-4-ylcarbamoyl)-2-ethyl-5,6,7,8-tetrahydrocyclohepta[b]pyrrol-1(4H)-yl]-3,5-dihydroxyheptanoic acid


Mass: 518.644 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H38N2O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 446 / 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: 2.22 Å3/Da / Density % sol: 44.53 %
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: Aug 7, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 1.7 % / Av σ(I) over netI: 12.4 / Number: 66699 / Rmerge(I) obs: 0.062 / Χ2: 1.08 / D res high: 2.4 Å / D res low: 50 Å / Num. obs: 39761 / % possible obs: 60.8
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
5.175065.410.0391.4221.7
4.15.1765.110.0540.9181.7
3.584.16510.060.9821.7
3.263.586510.0681.3111.7
3.023.2664.510.0830.9881.7
2.853.0264.410.10.8151.7
2.72.8562.910.1261.2271.7
2.592.758.310.1421.021.7
2.492.5952.310.1640.9891.6
2.42.4945.210.1661.1121.6
ReflectionResolution: 2.39→50 Å / Num. obs: 39761 / % possible obs: 60.8 % / Redundancy: 1.7 % / Rmerge(I) obs: 0.062 / Χ2: 1.082 / Net I/σ(I): 12.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.4-2.491.60.16629531.11245.2
2.49-2.591.60.16433910.98952.3
2.59-2.71.70.14238071.0258.3
2.7-2.851.70.12641211.22762.9
2.85-3.021.70.141680.81564.4
3.02-3.261.70.08342100.98864.5
3.26-3.581.70.06842561.31165
3.58-4.11.70.0642360.98265
4.1-5.171.70.05442880.91865.1
5.17-501.70.03943311.42265.4

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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: 2.39→50 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.893 / SU B: 12.73 / SU ML: 0.287 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.464 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.273 2011 5.1 %RANDOM
Rwork0.198 ---
obs0.201 39725 60.84 %-
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: 38.855 Å2
Baniso -1Baniso -2Baniso -3
1-1.24 Å20 Å2-1.19 Å2
2---2.63 Å20 Å2
3---0.25 Å2
Refinement stepCycle: LAST / Resolution: 2.39→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12552 0 172 446 13170
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.02112913
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211985
X-RAY DIFFRACTIONr_angle_refined_deg1.0061.98517455
X-RAY DIFFRACTIONr_angle_other_deg0.736327934
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.52151678
X-RAY DIFFRACTIONr_chiral_restr0.0560.21995
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0214380
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022389
X-RAY DIFFRACTIONr_nbd_refined0.1640.22907
X-RAY DIFFRACTIONr_nbd_other0.1970.214701
X-RAY DIFFRACTIONr_nbtor_other0.080.28012
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1550.2566
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1290.224
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1660.291
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1680.26
X-RAY DIFFRACTIONr_mcbond_it0.3041.58326
X-RAY DIFFRACTIONr_mcangle_it0.567213322
X-RAY DIFFRACTIONr_scbond_it0.65234587
X-RAY DIFFRACTIONr_scangle_it1.1714.54133
LS refinement shellResolution: 2.39→2.452 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.407 110
Rwork0.25 1952
all-2062

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