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- PDB-1mx1: Crystal Structure of Human Liver Carboxylesterase in complex with... -

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Basic information

Entry
Database: PDB / ID: 1mx1
TitleCrystal Structure of Human Liver Carboxylesterase in complex with tacrine
Componentsliver Carboxylesterase I
KeywordsHYDROLASE / esterase / esterase inhibitor
Function / homology
Function and homology information


cholesterol ester hydrolysis involved in cholesterol transport / methylumbelliferyl-acetate deacetylase / methylumbelliferyl-acetate deacetylase activity / sterol esterase / sterol esterase activity / medium-chain fatty acid metabolic process / regulation of bile acid secretion / positive regulation of cholesterol metabolic process / Physiological factors / carboxylesterase ...cholesterol ester hydrolysis involved in cholesterol transport / methylumbelliferyl-acetate deacetylase / methylumbelliferyl-acetate deacetylase activity / sterol esterase / sterol esterase activity / medium-chain fatty acid metabolic process / regulation of bile acid secretion / positive regulation of cholesterol metabolic process / Physiological factors / carboxylesterase / carboxylesterase activity / reverse cholesterol transport / cellular response to cholesterol / regulation of bile acid biosynthetic process / carboxylic ester hydrolase activity / Phase I - Functionalization of compounds / Aspirin ADME / cholesterol biosynthetic process / negative regulation of cholesterol storage / positive regulation of cholesterol efflux / cellular response to low-density lipoprotein particle stimulus / Metabolism of Angiotensinogen to Angiotensins / lipid catabolic process / cholesterol metabolic process / epithelial cell differentiation / lipid droplet / cholesterol homeostasis / response to toxic substance / endoplasmic reticulum lumen / endoplasmic reticulum / cytosol / cytoplasm
Similarity search - Function
Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
N-acetyl-alpha-neuraminic acid / TACRINE / Liver carboxylesterase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBencharit, S. / Morton, C.L. / Hyatt, J.L. / Kuhn, P. / Danks, M.K. / Potter, P.M. / Redinbo, M.R.
CitationJournal: CHEM.BIOL. / Year: 2003
Title: Crystal Structure of Human Carboxylesterase 1 Complexed with the Alzheimer's Drug Tacrine: From Binding Promiscuity to Selective Inhibition
Authors: Bencharit, S. / Morton, C.L. / Hyatt, J.L. / Kuhn, P. / Danks, M.K. / Potter, P.M. / Redinbo, M.R.
History
DepositionOct 1, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_alt_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Remark 300BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 6 CHAIN(S) ...BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 6 CHAIN(S). SEE REMARK 350 FOR INFORMATION ON GENERATING THE BIOLOGICAL MOLECULE(S). The authors have confirmed that human carboxylesterase 1 will form a trimer or hexamer in solution by Atomic Force Microscopy (AFM). They found the ratio of monomer:trimer:hexmer is ~ 10:44:46. 1MX5 is a trimer and 1MX9 is a hexamer. This entry contains a hexamer. The authors found that the trimer:hexmer ratio is dependent on the type and amount of ligands.
Remark 999SEQUENCE THE AUTHOR'S SEQUENCE HAS NO GLN 362 (CALLED hCEv in: Kroetz DL, McBride OW, Gonzalez FJ. ...SEQUENCE THE AUTHOR'S SEQUENCE HAS NO GLN 362 (CALLED hCEv in: Kroetz DL, McBride OW, Gonzalez FJ.Glycosylation-dependent activity of baculovirus-expressed human liver carboxylesterases: cDNA cloning and characterization of two highly similar enzyme forms. Biochemistry 1993 Nov 2;32(43):11606-17)

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: liver Carboxylesterase I
B: liver Carboxylesterase I
C: liver Carboxylesterase I
D: liver Carboxylesterase I
E: liver Carboxylesterase I
F: liver Carboxylesterase I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)367,24623
Polymers363,0686
Non-polymers4,17817
Water38,1382117
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24470 Å2
ΔGint-67 kcal/mol
Surface area106590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.021, 117.030, 176.010
Angle α, β, γ (deg.)90.00, 95.69, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe biological assembly is a hexamer formed by two trimers in one asymmetric unit

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Components

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Protein , 1 types, 6 molecules ABCDEF

#1: Protein
liver Carboxylesterase I / hCEv / Acyl coenzyme A:cholesterol acyltransferase / ACAT / Monocyte/macrophage serine esterase / ...hCEv / Acyl coenzyme A:cholesterol acyltransferase / ACAT / Monocyte/macrophage serine esterase / HMSE / Serine esterase 1


Mass: 60511.328 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): SF21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23141, carboxylesterase

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Sugars , 3 types, 11 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAca1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a2122h-1a_1-5_2*NCC/3=O]/1-2/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Sugar
ChemComp-SIA / N-acetyl-alpha-neuraminic acid / Sialic acid


Type: D-saccharide, alpha linking / Mass: 309.270 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C11H19NO9
IdentifierTypeProgram
DNeup5AcaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-a-D-neuraminic acidCOMMON NAMEGMML 1.0
a-D-Neup5AcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
Neu5AcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 2123 molecules

#5: Chemical
ChemComp-THA / TACRINE / Tacrine


Mass: 198.264 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C13H14N2 / Comment: inhibitor, agonist*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2117 / 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: 2.54 Å3/Da / Density % sol: 51.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: PEG3350, glycerol, lithium sulfate, sodium chloride, lithium chloride, sodium citrate, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 298.0K
Crystal grow
*PLUS
Temperature: 22 ℃ / pH: 7.4
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
13 mg/mlprotein1drop
250 mMHEPES1droppH7.4
310 Mtacrine1drop
410 %PEG33501reservoir
50.4 M1reservoirLi2SO4
60.1 M1reservoirNaCl
70.1 M1reservoirLiCl
80.1 Mcitrate1reservoirpH5.5
95 %glycerol1reservoir

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Feb 16, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→25 Å / Num. all: 141858 / Num. obs: 141040 / % possible obs: 7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 27.5 Å2
Reflection
*PLUS
Lowest resolution: 25 Å / Num. obs: 141078 / % possible obs: 99.5 % / Redundancy: 4 % / Num. measured all: 563091 / Rmerge(I) obs: 0.081
Reflection shell
*PLUS
Highest resolution: 2.4 Å / Lowest resolution: 2.42 Å / % possible obs: 99.9 % / Rmerge(I) obs: 0.231 / Mean I/σ(I) obs: 5.1

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
CNS1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→19.98 Å / Rfactor Rfree error: 0.002 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.207 9914 7 %RANDOM
Rwork0.162 ---
all0.1842 141858 --
obs0.162 141078 99.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 41.3681 Å2 / ksol: 0.351071 e/Å3
Displacement parametersBiso mean: 30.9 Å2
Baniso -1Baniso -2Baniso -3
1--2.33 Å20 Å25.75 Å2
2--2.27 Å20 Å2
3---0.06 Å2
Refine analyzeLuzzati coordinate error free: 0.28 Å / Luzzati sigma a free: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms24750 0 286 2117 27153
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d22.4
X-RAY DIFFRACTIONc_improper_angle_d0.76
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.007 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.265 1650 7 %
Rwork0.202 21898 -
obs--99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5THA.PARTHA.TOP
Refinement
*PLUS
Highest resolution: 2.4 Å / Lowest resolution: 25 Å / % reflection Rfree: 7 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.76
LS refinement shell
*PLUS
Highest resolution: 2.4 Å / Lowest resolution: 2.42 Å / Rfactor Rfree: 0.282 / Rfactor Rwork: 0.212

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