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- PDB-2r4f: Substituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors -

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Basic information

Entry
Database: PDB / ID: 2r4f
TitleSubstituted Pyrazoles as Hepatselective HMG-COA reductase inhibitors
Components3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA reductase
KeywordsOXIDOREDUCTASE / CHOLESTEROL / BIOCYNTHESIS / HMG-COA / NADPH / STATIN / Alternative splicing / Cholesterol biosynthesis / Endoplasmic reticulum / Glycoprotein / Lipid synthesis / Membrane / Peroxisome / Polymorphism / Steroid biosynthesis / Sterol 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 / 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-RIE / 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.7 Å
AuthorsPavlovsky, A. / Pfefferkorn, J.A. / Harris, M.S. / Finzel, B.C.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5- ...Title: Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
Authors: Pfefferkorn, J.A. / Choi, C. / Larsen, S.D. / Auerbach, B. / Hutchings, R. / Park, W. / Askew, V. / Dillon, L. / Hanselman, J.C. / Lin, Z. / Lu, G.H. / Robertson, A. / Sekerke, C. / Harris, ...Authors: Pfefferkorn, J.A. / Choi, C. / Larsen, S.D. / Auerbach, B. / Hutchings, R. / Park, W. / Askew, V. / Dillon, L. / Hanselman, J.C. / Lin, Z. / Lu, G.H. / Robertson, A. / Sekerke, C. / Harris, M.S. / Pavlovsky, A. / Bainbridge, G. / Caspers, N. / Kowala, M. / Tait, B.D.
History
DepositionAug 31, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 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 1.3Feb 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)192,40512
Polymers189,9184
Non-polymers2,4878
Water20,6811148
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area26010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.616, 135.334, 82.844
Angle α, β, γ (deg.)90.000, 97.530, 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 / 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-RIE / (3R,5R)-7-[1-(4-fluorophenyl)-4-(1-methylethyl)-3-{methyl[(1R)-1-phenylethyl]carbamoyl}-1H-pyrazol-5-yl]-3,5-dihydroxyheptanoic acid


Mass: 525.612 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H36FN3O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1148 / 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: 2.42 Å3/Da / Density % sol: 49.12 %

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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: Feb 10, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 186540 / % possible obs: 94 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.039 / Net I/σ(I): 25.6
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.295 / % possible all: 75.1

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Processing

Software
NameVersionClassificationNB
REFMAC5.1.24refinement
PDB_EXTRACT3data extraction
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.7→39.54 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.939 / SU B: 2.261 / SU ML: 0.076 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.124 / ESU R Free: 0.114 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.234 9404 5 %RANDOM
Rwork0.214 ---
obs0.215 186443 93.71 %-
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: 27.532 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: 1.7→39.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12054 0 172 1148 13374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.02212398
X-RAY DIFFRACTIONr_angle_refined_deg0.9771.99116760
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.43651614
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_restr0.0550.21929
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.029172
X-RAY DIFFRACTIONr_nbd_refined0.1640.26383
X-RAY DIFFRACTIONr_nbtor_refined0.2880.28692
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0670.21144
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0670.238
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0350.213
X-RAY DIFFRACTIONr_mcbond_it0.2461.58322
X-RAY DIFFRACTIONr_mcangle_it0.429212823
X-RAY DIFFRACTIONr_scbond_it0.56734636
X-RAY DIFFRACTIONr_scangle_it0.8914.53937
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.74 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.322 499 -
Rwork0.294 9425 -
all-9924 -
obs--67.64 %

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