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- PDB-4yes: Thrombin in complex with (S)-(4-chloro-2-((1-(5-methyl-1H-pyrrole... -

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Basic information

Entry
Database: PDB / ID: 4yes
TitleThrombin in complex with (S)-(4-chloro-2-((1-(5-methyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamido)methyl)phenyl)methanaminium
Components
  • Hirudin
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHydrolase/Hydrolase Inhibitor / Sulfo-hirudin / Inhibitor / Complex / Thrombin / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway ...negative regulation of serine-type peptidase activity / positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of platelet activation / negative regulation of astrocyte differentiation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / positive regulation of blood coagulation / negative regulation of fibrinolysis / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / regulation of cytosolic calcium ion concentration / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / negative regulation of proteolysis / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / response to wounding / Golgi lumen / positive regulation of protein localization to nucleus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / antimicrobial humoral immune response mediated by antimicrobial peptide / Thrombin signalling through proteinase activated receptors (PARs) / heparin binding / regulation of cell shape / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of cell population proliferation / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle ...Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Kringle-like fold / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(5-methyl-1H-pyrrol-2-yl)carbonyl]-L-prolinamide / Chem-45S / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsOrth, P.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.
Authors: Chobanian, H.R. / Pio, B. / Guo, Y. / Shen, H. / Huffman, M.A. / Madeira, M. / Salituro, G. / Terebetski, J.L. / Ormes, J. / Jochnowitz, N. / Hoos, L. / Zhou, Y. / Lewis, D. / Hawes, B. / ...Authors: Chobanian, H.R. / Pio, B. / Guo, Y. / Shen, H. / Huffman, M.A. / Madeira, M. / Salituro, G. / Terebetski, J.L. / Ormes, J. / Jochnowitz, N. / Hoos, L. / Zhou, Y. / Lewis, D. / Hawes, B. / Mitnaul, L. / O'Neill, K. / Ellsworth, K. / Wang, L. / Biftu, T. / Duffy, J.L.
History
DepositionFeb 24, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp / entity ...chem_comp / entity / entity_src_gen / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_entity_src_syn / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_nonpoly.name / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.conn_type_id / _struct_conn.id / _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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thrombin light chain
B: Thrombin heavy chain
H: Hirudin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1647
Polymers35,4513
Non-polymers7124
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3790 Å2
ΔGint-18 kcal/mol
Surface area12840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.770, 71.190, 72.810
Angle α, β, γ (deg.)90.000, 100.640, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 2 types, 2 molecules AH

#1: Protein/peptide Thrombin light chain / / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin / / Hirudin-1 / Hirudin-I / Lepirudin


Mass: 1574.618 Da / Num. of mol.: 1 / Fragment: UNP residues 54-65 / Source method: obtained synthetically / Details: AC-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tys-Leu-Gln / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P01050

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Protein / Sugars , 2 types, 2 molecules B

#2: Protein Thrombin heavy chain / / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
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

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Non-polymers , 4 types, 234 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-45S / N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(5-methyl-1H-pyrrol-2-yl)carbonyl]-L-prolinamide


Type: Peptide-like / Class: Inhibitor / Mass: 374.865 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23ClN4O2
References: N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(5-methyl-1H-pyrrol-2-yl)carbonyl]-L-prolinamide
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.62 Å3/Da / Density % sol: 53.13 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 28 % PEG 2000 MMe, 100mM BisTris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 53201 / % possible obs: 95.4 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.053 / Χ2: 1.041 / Net I/av σ(I): 21.332 / Net I/σ(I): 9.7 / Num. measured all: 177031
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.5-1.5530.5471.844720.934180.2
1.55-1.623.10.4452.450200.95390.7
1.62-1.693.20.3353.353081.03195.8
1.69-1.783.30.2424.654381.06997
1.78-1.893.50.1726.953681.17397.2
1.89-2.043.50.117954061.09797.3
2.04-2.243.30.08411.554721.05498.1
2.24-2.563.50.06814.755051.0198.6
2.56-3.233.40.0519.155461.04999
3.23-503.40.03727.356660.99599.5

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.4refinement
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
DENZOdata reduction
BUSTER2.11.4refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1A2C

1a2c


Resolution: 1.5→21.96 Å / Cor.coef. Fo:Fc: 0.9499 / Cor.coef. Fo:Fc free: 0.9367 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1067 2.01 %RANDOM
Rwork0.209 ---
obs0.2095 53182 94.95 %-
Displacement parametersBiso max: 102.4 Å2 / Biso mean: 30.4147 Å2 / Biso min: 12.7 Å2
Baniso -1Baniso -2Baniso -3
1--6.9952 Å20 Å23.6111 Å2
2--3.3912 Å20 Å2
3---3.604 Å2
Refine analyzeLuzzati coordinate error obs: 0.228 Å
Refinement stepCycle: LAST / Resolution: 1.5→21.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2343 0 47 231 2621
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d850SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes61HARMONIC2
X-RAY DIFFRACTIONt_gen_planes354HARMONIC5
X-RAY DIFFRACTIONt_it2451HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion301SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2915SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2451HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3318HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion3.81
X-RAY DIFFRACTIONt_other_torsion15.31
LS refinement shellResolution: 1.5→1.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3098 72 2.37 %
Rwork0.267 2972 -
all0.268 3044 -
obs--94.95 %

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