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- PDB-1dwc: CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BIND... -

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Entry
Database: PDB / ID: 1dwc
TitleCRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS
Components
  • ALPHA-THROMBIN (LARGE SUBUNIT)
  • ALPHA-THROMBIN (SMALL SUBUNIT)
  • HIRUDIN IIIA
KeywordsHYDROLASE/HYROLASE INHIBITOR / SERINE PROTEINASE / HYDROLASE-HYROLASE INHIBITOR COMPLEX
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
Argatroban / Chem-MIT / Prothrombin / Hirudin-2 / Hirudin-3A'
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / Resolution: 3 Å
AuthorsBanner, D.W. / Hadvary, P.
Citation
Journal: J.Biol.Chem. / Year: 1991
Title: Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors.
Authors: Banner, D.W. / Hadvary, P.
#1: Journal: Eur.J.Biochem. / Year: 1990
Title: Geometry of binding of the benzamidine- and arginine-based inhibitors N alpha-(2-naphthyl-sulphonyl-glycyl)-DL-p-amidinophenylalanyl-pipe ridine (NAPAP) and (2R,4R)-4-methyl-1-[N alpha-(3- ...Title: Geometry of binding of the benzamidine- and arginine-based inhibitors N alpha-(2-naphthyl-sulphonyl-glycyl)-DL-p-amidinophenylalanyl-pipe ridine (NAPAP) and (2R,4R)-4-methyl-1-[N alpha-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid (MQPA) to human alpha-thrombin. X-ray crystallographic determination of the NAPAP-trypsin complex and modeling of NAPAP-thrombin and MQPA-thrombin.
Authors: Bode, W. / Turk, D. / Sturzebecher, J.
#2: Journal: Embo J. / Year: 1989
Title: The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment.
Authors: Bode, W. / Mayr, I. / Baumann, U. / Huber, R. / Stone, S.R. / Hofsteenge, J.
#3: Journal: Protein Sci. / Year: 1992
Title: The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active- ...Title: The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships.
Authors: Bode, W. / Turk, D. / Karshikov, A.
#4: Journal: Science / Year: 1990
Title: The structure of a complex of recombinant hirudin and human alpha-thrombin.
Authors: Rydel, T.J. / Ravichandran, K.G. / Tulinsky, A. / Bode, W. / Huber, R. / Roitsch, C. / Fenton, J.W.
#5: Journal: Eur.J.Biochem. / Year: 1992
Title: The interaction of thrombin with fibrinogen. A structural basis for its specificity.
Authors: Stubbs, M.T. / Oschkinat, H. / Mayr, I. / Huber, R. / Angliker, H. / Stone, S.R. / Bode, W.
#6: Journal: Embo J. / Year: 1990
Title: Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition.
Authors: Grutter, M.G. / Priestle, J.P. / Rahuel, J. / Grossenbacher, H. / Bode, W. / Hofsteenge, J. / Stone, S.R.
History
DepositionAug 19, 1992Processing site: BNL
Revision 1.0Jan 31, 1994Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Jun 5, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.process_site / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: ALPHA-THROMBIN (SMALL SUBUNIT)
H: ALPHA-THROMBIN (LARGE SUBUNIT)
I: HIRUDIN IIIA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7984
Polymers35,2883
Non-polymers5101
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4190 Å2
ΔGint-20 kcal/mol
Surface area13380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.800, 90.800, 132.500
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Atom site foot note1: CIS PROLINE - PRO H 37
2: PHE H 245 - GLY H 246 OMEGA =359.98 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION
3: LEU I 10 - GLN I 11 OMEGA = 0.00 PEPTIDE BOND DEVIATES SIGNIFICANTLY FROM TRANS CONFORMATION
4: RESIDUE ASN H 60G IS GLYCOSYLATED. THE SUGAR ELECTRON DENSITY IS WEAK AND NO COORDINATES ARE PRESENT FOR THE SUGAR.

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Components

#1: Protein/peptide ALPHA-THROMBIN (SMALL SUBUNIT)


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Organ: PLASMA / References: UniProt: P00734, thrombin
#2: Protein ALPHA-THROMBIN (LARGE SUBUNIT)


Mass: 29780.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Organ: PLASMA / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUDIN IIIA


Mass: 1411.465 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28508, UniProt: P28504*PLUS
#4: Chemical ChemComp-MIT / amino{[(4S)-5-[(2R,4R)-2-carboxy-4-methylpiperidin-1-yl]-4-({[(3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}amino)-5-oxopentyl]amino}methaniminium / R-argatroban / MQPA / MD-805 / MITSUBISHI INHIBITOR


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 509.642 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H37N6O5S / References: Argatroban
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN INDICATOR *L* IS USED FOR RESIDUES 1H - 15 ...THROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN INDICATOR *L* IS USED FOR RESIDUES 1H - 15 AND CHAIN INDICATOR *H* IS USED FOR RESIDUES 16 - 247. CHAIN INDICATOR *I* IS USED FOR A C-TERMINAL HIRUDIN PEPTIDE ((DES-AMINO ASP55)HIRUDIN(55-65)). THE RESIDUES OF CHAIN I ARE NUMBERED FROM 1 - 11. IT BINDS IN THE ANION-BINDING EXOSITE.
Has protein modificationY
Nonpolymer detailsTHE INHIBITOR QUINOLINE IS A MIXTURE OF STEREOISOMERS. THE AUTHORS CANNOT DETERMINE AT THIS ...THE INHIBITOR QUINOLINE IS A MIXTURE OF STEREOISOMERS. THE AUTHORS CANNOT DETERMINE AT THIS RESOLUTION WHICH STEREOISOMER BINDS AND THUS HAVE TAKEN AN ARBITRARY ISOMER FOR REFINEMENT. THE OTHER STEREO CENTERS ARE WELL DEFINED. MD-805 (AGRATROBAN) IS ((2R,4R)-4-METHYL-1[N==ALPHA==- [3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINYL)SULPHONYL]- L-ARGINYL)]-2-PIPERIDINECARBOXYLIC ACID).

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.87 Å3/Da / Density % sol: 68.2 %
Crystal grow
*PLUS
pH: 7.5 / Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
125 %PEG40001reservoir
2200 mM1reservoirCaCl2
3100 mMHEPES1reservoir
4precipitant1reservoir
5protein1drop

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Data collection

RadiationScattering type: x-ray
Radiation wavelengthRelative weight: 1
Reflection
*PLUS
Highest resolution: 2.58 Å / Lowest resolution: 9999 Å / Num. obs: 11775 / Num. measured all: 21259 / Rmerge(I) obs: 0.066

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Processing

SoftwareName: TNT / Classification: refinement
RefinementResolution: 3→25 Å / Rfactor obs: 0.15 / σ(F): 0
Details: PROLINES ARE TOO FLAT AS A BAD DICTIONARY WAS USED. RESIDUE ASN H 60G IS GLYCOSYLATED. THE SUGAR ELECTRON DENSITY IS WEAK AND NO COORDINATES ARE PRESENT FOR THE SUGAR
Refinement stepCycle: LAST / Resolution: 3→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 35 50 2437
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONt_bond_d0.014
X-RAY DIFFRACTIONt_angle_deg1.94
X-RAY DIFFRACTIONt_dihedral_angle_d
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes
X-RAY DIFFRACTIONt_it
X-RAY DIFFRACTIONt_nbd
Refinement
*PLUS
Highest resolution: 3 Å / Lowest resolution: 25 Å / Num. reflection all: 8370 / σ(F): 0 / Rfactor all: 0.15
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDType
X-RAY DIFFRACTIONt_angle_d
X-RAY DIFFRACTIONt_angle_deg

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