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- PDB-2q6c: Design and synthesis of novel, conformationally restricted HMG-CO... -

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Basic information

Entry
Database: PDB / ID: 2q6c
TitleDesign and synthesis of novel, conformationally restricted HMG-COA reductase inhibitors
Components3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA reductase
KeywordsOXIDOREDUCTASE / CHOLESTEROL BIOSYNTHESIS / HMG-COA / NADPH / STATIN
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 / coenzyme A metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / 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 / coenzyme A metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / 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 / negative regulation of protein catabolic process / PPARA activates gene expression / 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-HR1 / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsPavlovsky, A. / Pfefferkorn, J.A. / Harris, M.S. / Finzel, B.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Design and synthesis of novel, conformationally restricted HMG-CoA reductase inhibitors.
Authors: Pfefferkorn, J.A. / Choi, C. / Song, Y. / Trivedi, B.K. / Larsen, S.D. / Askew, V. / Dillon, L. / Hanselman, J.C. / Lin, Z. / Lu, G. / Robertson, A. / Sekerke, C. / Auerbach, B. / Pavlovsky, ...Authors: Pfefferkorn, J.A. / Choi, C. / Song, Y. / Trivedi, B.K. / Larsen, S.D. / Askew, V. / Dillon, L. / Hanselman, J.C. / Lin, Z. / Lu, G. / Robertson, A. / Sekerke, C. / Auerbach, B. / Pavlovsky, A. / Harris, M.S. / Bainbridge, G. / Caspers, N.
History
DepositionJun 4, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 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 1.4Oct 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 1.5Feb 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)192,52912
Polymers189,9184
Non-polymers2,6118
Water20,1771120
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area28150 Å2
ΔGint-237 kcal/mol
Surface area55550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.816, 135.367, 83.121
Angle α, β, γ (deg.)90.00, 97.02, 90.00
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 / 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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-HR1 / (3R,5R)-7-[1-(4-FLUOROPHENYL)-3-ISOPROPYL-4-OXO-5-PHENYL-4,5-DIHYDRO-3H-PYRROLO[2,3-C]QUINOLIN-2-YL]-3,5-DIHYDROXYHEPTANOIC ACID


Mass: 556.624 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H33FN2O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1120 / 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: 2.43 Å3/Da / Density % sol: 49.46 %
Crystal growMethod: vapor diffusion / Details: VAPOR DIFFUSION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
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
ReflectionResolution: 2→50 Å / Num. obs: 116834 / % possible obs: 95.4 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.054 / Χ2: 1 / Net I/σ(I): 12.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2-2.073.50.319104280.87285.3
2.07-2.153.50.243110380.9790.8
2.15-2.253.50.189113951.11693.2
2.25-2.373.50.148116331.19695.1
2.37-2.523.60.119118451.14696.9
2.52-2.713.70.093119041.06697.8
2.71-2.993.80.07120350.91498.3
2.99-3.423.90.05120630.82798.7
3.42-4.313.90.036121661.11799
4.31-503.80.033123270.81299.3

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.1.24refinement
PDB_EXTRACT2data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→50 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.917 / SU B: 4.461 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.222 / ESU R Free: 0.183 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25158 5875 5 %RANDOM
Rwork0.21745 ---
obs0.21917 110925 --
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: 26.705 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å20 Å21.29 Å2
2--0.77 Å20 Å2
3----0.67 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12416 0 184 1120 13720
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.02112791
X-RAY DIFFRACTIONr_bond_other_d0.0020.0211826
X-RAY DIFFRACTIONr_angle_refined_deg1.0751.98717307
X-RAY DIFFRACTIONr_angle_other_deg0.709327553
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.81551662
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0520.21975
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0214263
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022381
X-RAY DIFFRACTIONr_nbd_refined0.160.22677
X-RAY DIFFRACTIONr_nbd_other0.1970.214308
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0780.27662
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1010.2745
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0650.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1220.253
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0530.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.2661.58246
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.505213188
X-RAY DIFFRACTIONr_scbond_it0.63134545
X-RAY DIFFRACTIONr_scangle_it1.1344.54119
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.278 375
Rwork0.255 7132

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