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- PDB-6rot: Thrombin in complex with MI2105 -

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Basic information

Entry
Database: PDB / ID: 6rot
TitleThrombin in complex with MI2105
Components
  • (Prothrombin) x 2
  • Hirudin variant-2
KeywordsHYDROLASE / COAGULATION / BLOOD CLOTTING / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / THROMBIN INHIBITOR / PREORGANIZATION / GLYCOSYLATION / BLOOD
Function / homology
Function and homology information


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 / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin ...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 / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / negative regulation of platelet activation / 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 / acute-phase response / Regulation of Complement cascade / negative regulation of proteolysis / Cell surface interactions at the vascular wall / lipopolysaccharide binding / 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 / positive regulation of protein localization to nucleus / Golgi lumen / antimicrobial humoral immune response mediated by antimicrobial peptide / 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 / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / blood microparticle / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / 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
Chem-KDQ / PHOSPHATE ION / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.339 Å
AuthorsSandner, A. / Heine, A. / Klebe, G.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding.
Authors: Sandner, A. / Hufner-Wulsdorf, T. / Heine, A. / Steinmetzer, T. / Klebe, G.
History
DepositionMay 13, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Refinement description / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / refine / 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_alt_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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_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.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _refine.pdbx_diffrn_id / _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_ptnr1_label_alt_id / _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_conn.ptnr2_symmetry
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Jan 24, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Prothrombin
H: Prothrombin
A: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,93011
Polymers34,8543
Non-polymers1,0778
Water4,414245
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4470 Å2
ΔGint-32 kcal/mol
Surface area12600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.926, 71.177, 73.006
Angle α, β, γ (deg.)90.00, 100.72, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-75-

ARG

21H-406-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LA

#1: Protein/peptide Prothrombin / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Plasmid details: purified from human blood tissue / Tissue: Blood / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-2


Mass: 1548.580 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: https://shop.bachem.com/4014553.html cotains sulfated tyrosine
Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Prothrombin / Coagulation factor II


Mass: 29208.572 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Plasmid details: purified from human blood tissue / Tissue: Blood / References: UniProt: P00734, thrombin
#5: 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, 252 molecules

#4: Chemical ChemComp-KDQ / (2~{S})-~{N}-[[5-chloranyl-2-(hydroxymethyl)phenyl]methyl]-1-[2-[(phenylmethyl)sulfonylamino]ethanoyl]pyrrolidine-2-carboxamide


Mass: 479.977 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26ClN3O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 245 / 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: 2.48 Å3/Da / Density % sol: 50 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20mM sodium dihydrogen phosphate ph 7.5 350mM NaCl 27% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 31, 2019 / Details: Signally bended Si111-crystal
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.34→43.52 Å / Num. obs: 77800 / % possible obs: 98.5 % / Redundancy: 3.4 % / CC1/2: 1 / Rsym value: 0.044 / Net I/σ(I): 16.6
Reflection shellResolution: 1.34→1.42 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 2.31 / Num. unique obs: 12438 / CC1/2: 0.81 / Rsym value: 0.59 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
Cootmodel building
XDSdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H8D

1h8d


Resolution: 1.339→43.516 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 15.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1574 3890 5 %
Rwork0.1371 --
obs0.1381 77794 98.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.339→43.516 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2303 0 65 245 2613
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082591
X-RAY DIFFRACTIONf_angle_d1.0423528
X-RAY DIFFRACTIONf_dihedral_angle_d20.1531005
X-RAY DIFFRACTIONf_chiral_restr0.086366
X-RAY DIFFRACTIONf_plane_restr0.007472
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3391-1.35540.27581320.23582518X-RAY DIFFRACTION95
1.3554-1.37260.25391380.21542623X-RAY DIFFRACTION98
1.3726-1.39060.23231390.2122645X-RAY DIFFRACTION99
1.3906-1.40970.24221380.1992606X-RAY DIFFRACTION98
1.4097-1.42980.21061410.19622685X-RAY DIFFRACTION98
1.4298-1.45120.19581360.17782579X-RAY DIFFRACTION99
1.4512-1.47380.20911400.17192668X-RAY DIFFRACTION99
1.4738-1.4980.22381390.16092637X-RAY DIFFRACTION99
1.498-1.52380.16541380.15952624X-RAY DIFFRACTION98
1.5238-1.55150.1861390.142631X-RAY DIFFRACTION99
1.5515-1.58140.16011380.12842635X-RAY DIFFRACTION99
1.5814-1.61370.19241400.13182664X-RAY DIFFRACTION99
1.6137-1.64880.15911400.11912646X-RAY DIFFRACTION99
1.6488-1.68710.14871370.12022608X-RAY DIFFRACTION99
1.6871-1.72930.15651410.11612690X-RAY DIFFRACTION99
1.7293-1.77610.13481380.11572609X-RAY DIFFRACTION98
1.7761-1.82830.13711390.11722649X-RAY DIFFRACTION99
1.8283-1.88730.14111390.11932638X-RAY DIFFRACTION98
1.8873-1.95480.12981360.11692587X-RAY DIFFRACTION97
1.9548-2.03310.11131410.11582680X-RAY DIFFRACTION99
2.0331-2.12560.12521400.11852650X-RAY DIFFRACTION99
2.1256-2.23760.14591390.11622644X-RAY DIFFRACTION99
2.2376-2.37780.14981410.12592673X-RAY DIFFRACTION99
2.3778-2.56140.15571380.12842624X-RAY DIFFRACTION99
2.5614-2.81910.17141370.13962609X-RAY DIFFRACTION97
2.8191-3.22690.1581410.14882676X-RAY DIFFRACTION99
3.2269-4.06510.15661420.13382696X-RAY DIFFRACTION99
4.0651-43.53940.15371430.152710X-RAY DIFFRACTION98

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