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- PDB-4udw: Thrombin in complex with 1-(2R)-2-amino-3-phenyl-propanoyl-N-(2, ... -

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Basic information

Entry
Database: PDB / ID: 4udw
TitleThrombin in complex with 1-(2R)-2-amino-3-phenyl-propanoyl-N-(2, 5dichlorophenyl)methylpyrrolidine-2-carboxamide
Components
  • HIRUDIN VARIANT-2
  • THROMBIN HEAVY CHAIN
  • THROMBIN LIGHT CHAIN
KeywordsHYDROLASE / HYDROLASE INHIBITOR COMPLEX / SERINE PROTEASE / BLOOD COAGULATION / BLOOD CLOTTING / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / THROMBIN INHIBITOR / FRAGMENT / GLYCOSYLATION / BLOOD
Function / homology
Function and homology information


cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin ...cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / regulation of cytosolic calcium ion concentration / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of proteolysis / negative regulation of cytokine production involved in inflammatory response / Peptide ligand-binding receptors / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / lipopolysaccharide binding / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / 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 / regulation of cell shape / heparin binding / Thrombin signalling through proteinase activated receptors (PARs) / : / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / positive regulation of cell population proliferation / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain ...Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / 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
Chem-N6L / PHOSPHATE ION / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.16 Å
AuthorsRuehmann, E. / Heine, A. / Klebe, G.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragments Can Bind Either More Enthalpy or Entropy-Driven: Crystal Structures and Residual Hydration Pattern Suggest Why.
Authors: Ruehmann, E. / Betz, M. / Heine, A. / Klebe, G.
History
DepositionDec 12, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2015Group: Database references
Revision 1.2Mar 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 2.0Oct 23, 2019Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Other
Category: atom_site / pdbx_database_status ...atom_site / pdbx_database_status / pdbx_struct_special_symmetry / struct_conn
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 / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag
Revision 2.1Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_ptnr2_PDB_ins_code / _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 2.2Dec 20, 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 2.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "HB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "HB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: THROMBIN HEAVY CHAIN
I: HIRUDIN VARIANT-2
L: THROMBIN LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3359
Polymers34,4603
Non-polymers8756
Water5,567309
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4240 Å2
ΔGint-37.5 kcal/mol
Surface area12620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.640, 71.106, 72.327
Angle α, β, γ (deg.)90.00, 100.44, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-75-

ARG

21H-75-

ARG

31H-2096-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules IL

#2: Protein/peptide HIRUDIN VARIANT-2


Mass: 1491.528 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 62-72 / Source method: obtained synthetically / Details: HIRUDIN (54-65) (SULFATED) / Source: (synth.) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P09945
#3: Protein/peptide THROMBIN LIGHT CHAIN / COAGULATION FACTOR II / ACTIVATION PEPTIDE FRAGMENT 1 / ACTIVATION PEPTIDE FRAGMENT 2 / THROMBIN ALPHA


Mass: 3317.741 Da / Num. of mol.: 1 / Fragment: THROMBIN LIGHT CHAIN, UNP RESIDUES 333-360 / Source method: isolated from a natural source / Details: PURIFIED FROM HUMAN BLOOD PLASMA / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00734, thrombin

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Protein / Sugars , 2 types, 2 molecules H

#1: Protein THROMBIN HEAVY CHAIN / COAGULATION FACTOR II / ACTIVATION PEPTIDE FRAGMENT 1 / ACTIVATION PEPTIDE FRAGMENT 2 / THROMBIN ALPHA


Mass: 29651.105 Da / Num. of mol.: 1 / Fragment: THROMBIN HEAVY CHAIN, UNP RESIDUES 364-620 / Source method: isolated from a natural source / Details: PURIFIED FROM HUMAN BLOOD PLASMA / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00734, thrombin
#8: 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


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 , 5 types, 314 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-N6L / D-phenylalanyl-N-(2,5-dichlorobenzyl)-L-prolinamide


Mass: 420.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23Cl2N3O2
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 309 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsASP 14L WAS NOT BUILD DUE TO LACK OF ELECTRON DESITY RESIDUES 148-149E WERE NOT BUILD DUE TO LACK ...ASP 14L WAS NOT BUILD DUE TO LACK OF ELECTRON DESITY RESIDUES 148-149E WERE NOT BUILD DUE TO LACK OF ELECTRON DESITY GLY 554 WAS NOT BUILD DUE TO LACK OF ELECTRON DESITY

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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: 2.45 Å3/Da / Density % sol: 49.7 % / Description: NONE
Crystal growpH: 7.5
Details: SEE MATERIALS AND METHODS SECTION OF PUBLICATION, pH 7.5

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.976
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.16→71.13 Å / Num. obs: 116096 / % possible obs: 97 % / Observed criterion σ(I): 2.7 / Redundancy: 4.4 % / Biso Wilson estimate: 13.15 Å2 / Rmerge(I) obs: 0.02 / Net I/σ(I): 25.92
Reflection shellResolution: 1.16→1.2 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.7 / % possible all: 87.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H8D

1h8d


Resolution: 1.16→71.131 Å / SU ML: 0.08 / σ(F): 1.35 / Phase error: 13.07 / Stereochemistry target values: ML / Details: DISORDERED REGIONS WERE NOT MODELED
RfactorNum. reflection% reflection
Rfree0.1413 5801 5 %
Rwork0.1238 --
obs0.1247 116082 97.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21 Å2
Refinement stepCycle: LAST / Resolution: 1.16→71.131 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2330 0 55 309 2694
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122573
X-RAY DIFFRACTIONf_angle_d1.5063497
X-RAY DIFFRACTIONf_dihedral_angle_d15.4991024
X-RAY DIFFRACTIONf_chiral_restr0.092365
X-RAY DIFFRACTIONf_plane_restr0.009451
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1599-1.1730.23881660.22073185X-RAY DIFFRACTION86
1.173-1.18680.22641770.21583347X-RAY DIFFRACTION88
1.1868-1.20130.22391780.20333398X-RAY DIFFRACTION90
1.2013-1.21650.23781850.18943496X-RAY DIFFRACTION93
1.2165-1.23250.18631850.17613521X-RAY DIFFRACTION94
1.2325-1.24940.18371930.16813679X-RAY DIFFRACTION96
1.2494-1.26730.18181920.15273651X-RAY DIFFRACTION97
1.2673-1.28620.16751920.14423654X-RAY DIFFRACTION97
1.2862-1.30630.15231940.1373680X-RAY DIFFRACTION98
1.3063-1.32770.14581930.13183690X-RAY DIFFRACTION98
1.3277-1.35060.16991940.12873694X-RAY DIFFRACTION98
1.3506-1.37520.1321940.11973678X-RAY DIFFRACTION98
1.3752-1.40160.14831960.11653723X-RAY DIFFRACTION98
1.4016-1.43020.13561940.11113693X-RAY DIFFRACTION98
1.4302-1.46130.14591960.10353720X-RAY DIFFRACTION98
1.4613-1.49530.14011950.0993707X-RAY DIFFRACTION98
1.4953-1.53270.11441960.09383726X-RAY DIFFRACTION99
1.5327-1.57420.12071960.08853734X-RAY DIFFRACTION99
1.5742-1.62050.11171970.08983753X-RAY DIFFRACTION99
1.6205-1.67280.11111970.08883737X-RAY DIFFRACTION99
1.6728-1.73260.11171980.08953764X-RAY DIFFRACTION99
1.7326-1.8020.1191950.09483704X-RAY DIFFRACTION99
1.802-1.8840.1312000.10193799X-RAY DIFFRACTION100
1.884-1.98330.13242010.10443824X-RAY DIFFRACTION100
1.9833-2.10760.13361980.10953745X-RAY DIFFRACTION100
2.1076-2.27030.1281990.11213790X-RAY DIFFRACTION99
2.2703-2.49880.15351990.11913773X-RAY DIFFRACTION99
2.4988-2.86040.15161970.1323758X-RAY DIFFRACTION99
2.8604-3.60380.14842010.14053805X-RAY DIFFRACTION99
3.6038-71.26470.13522030.14123853X-RAY DIFFRACTION99

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