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- PDB-6t89: Thrombin in complex with (S)-N-(tert-butyl)-4-(3-(3-carbamimidoyl... -

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Basic information

Entry
Database: PDB / ID: 6t89
TitleThrombin in complex with (S)-N-(tert-butyl)-4-(3-(3-carbamimidoylphenyl)-2-((2',4'-dimethoxy-[1,1'-biphenyl])-3-sulfonamido)propanoyl)piperazine-1-carboxamide (MI-498)
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


cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin-activated receptor signaling pathway / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / Defective F8 cleavage by thrombin / ligand-gated ion channel signaling pathway ...cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin-activated receptor signaling pathway / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / Defective F8 cleavage by thrombin / ligand-gated ion channel signaling pathway / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / 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 / negative regulation of proteolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of cytokine production involved in inflammatory response / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / Regulation of Complement cascade / acute-phase response / positive regulation of receptor signaling pathway via JAK-STAT / Cell surface interactions at the vascular wall / lipopolysaccharide binding / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / positive regulation of protein localization to nucleus / response to wounding / 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 / heparin binding / regulation of cell shape / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of protein phosphorylation / positive regulation of cell growth / : / G alpha (q) signalling events / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / 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-MUQ / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsNgaha, S.A. / Sandner, A. / Huber, S. / Heine, A. / Steinmetzer, T. / Pilgram, O.
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Improving the selectivity of 3-amidinophenylalanine-derived matriptase inhibitors
Authors: Pilgram, O. / Keils, A. / Benary, G.E. / Muller, J. / Merkl, S. / Ngaha, S. / Huber, S. / Chevillard, F. / Harbig, A. / Magdolen, V. / Heine, A. / Bottcher-Friebertshauser, E. / Steinmetzer, T.
History
DepositionOct 24, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)36,3658
Polymers35,4253
Non-polymers9405
Water3,153175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3980 Å2
ΔGint-29 kcal/mol
Surface area12190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.914, 71.829, 72.158
Angle α, β, γ (deg.)90.000, 100.950, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-75-

ARG

21H-75-

ARG

31H-413-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#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: 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/4014557.html contains 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: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Plasmid details: purified from human blood / 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 , 4 types, 179 molecules

#4: Chemical ChemComp-MUQ / 4-[(2~{S})-3-(3-carbamimidoylphenyl)-2-[[3-(4-methoxy-2-oxidanyl-phenyl)phenyl]sulfonylamino]propanoyl]-~{N}-methyl-piperazine-1-carboxamide


Mass: 594.682 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34N6O6S
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 175 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationY

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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: 2.92 Å3/Da / Density % sol: 57.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20 mM sodium dihydrogen phosphate ph 7.5 350 mM NaCl 27 % PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: May 17, 2018 / Details: Sagitally 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: 2→43.95 Å / Num. obs: 24300 / % possible obs: 98.7 % / Redundancy: 3.5 % / CC1/2: 0.99 / Rsym value: 0.1 / Net I/σ(I): 8.24
Reflection shellResolution: 2→2.12 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 2.09 / Num. unique obs: 3865 / CC1/2: 0.78 / Rsym value: 0.54 / % possible all: 97.2

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1h8d

1h8d


Resolution: 2→35.422 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.32 / Details: phenix refinement
RfactorNum. reflection% reflection
Rfree0.2152 1215 5 %
Rwork0.172 --
obs0.1741 24293 98.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 72.24 Å2 / Biso mean: 32.0044 Å2 / Biso min: 14.95 Å2
Refinement stepCycle: final / Resolution: 2→35.422 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 62 176 2505
Biso mean--40.32 37.21 -
Num. residues----289
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2-2.07570.27621290.2411246696
2.0757-2.17010.25751370.20772592100
2.1701-2.28450.22491350.19742568100
2.2845-2.42760.23921370.18332599100
2.4276-2.6150.22441330.1836253499
2.615-2.87810.23441360.1872257599
2.8781-3.29430.21931330.1844252997
3.2943-4.14940.21151360.1416257899
4.1494-35.420.17531390.1537263799
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.04971.82940.47298.4994-2.80745.52470.2334-0.1747-0.3389-0.2181-0.02070.92820.2602-0.4025-0.17540.19360.0097-0.03540.2234-0.03590.27081.12290.597517.376
25.46782.4151-0.20245.66761.68885.50280.19870.4194-0.2579-0.563-0.29030.03840.4520.03950.10490.29840.1-0.04460.3029-0.01480.190415.2368-1.21018.4558
32.9253-2.73911.90122.6516-2.01931.89940.39610.2675-0.08-0.513-0.2753-0.19660.12850.2247-0.07460.26280.06680.02840.3127-0.00030.225623.8887-6.960614.1176
41.4095-0.25860.75742.794-1.35532.11090.31340.3073-0.252-0.6056-0.26020.24620.310.1583-0.06320.40910.1216-0.07820.3393-0.06780.22819.04560.63323.4746
52.7006-1.50230.50372.4431-0.03871.59090.05410.13290.15880.0526-0.0817-0.1976-0.04550.27660.02870.2112-0.0066-0.01490.23050.01170.222418.31213.265219.9286
62.3574-0.27060.66154.2065-0.46943.53890.07-0.0257-0.5053-0.3830.09070.66030.3362-0.3374-0.1110.2471-0.0044-0.03590.20230.00120.35594.1986-7.246620.326
72.57824.0111-2.72147.6094-5.04544.9142-0.0017-0.3924-0.14850.5527-0.0661-0.3840.06190.30690.0690.3630.0547-0.01480.29560.03830.252818.8728-10.535435.6357
82.112-1.43010.23662.77740.13582.2097-0.0561-0.1686-0.20940.17270.06560.26650.1099-0.0784-0.00910.2260.00430.01690.22490.02330.21588.4641-0.922127.3664
95.34983.54440.06636.7254-0.82274.29190.0081-0.0942-0.38370.33640.3110.50230.6267-0.0709-0.29740.26920.0539-0.00320.19520.05580.304311.525-10.490228.5652
108.93252.4927-4.04815.2893-1.93966.4507-0.04660.00740.48320.1129-0.1185-1.0199-0.5950.66910.09590.2504-0.0548-0.01340.27590.02410.459626.61478.448622.7849
118.47676.16467.07217.21486.22987.6943-0.04930.3107-0.0178-0.19510.2015-0.1319-0.46730.2206-0.06870.31740.03960.01480.20640.0330.23545.257614.820318.2388
126.3968-0.36842.45573.0296-2.90463.62340.0752-0.35610.10940.3192-0.01650.7632-0.3482-0.5131-0.14490.17860.05960.04630.2737-0.03370.254-3.394312.279720.8927
137.97830.37117.28432.143-0.07687.4801-0.4904-1.05520.11850.4195-0.01770.4890.2071-0.66110.51870.33240.07090.13330.34010.03980.3372-0.69335.756232.3488
140.3418-0.43640.59792.29191.28663.47010.34580.5957-0.1674-0.696-0.0914-0.0443-0.08170.29170.15920.68570.2047-0.06760.6542-0.12190.26511.4837-1.5572-2.8453
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'H' and (resid 30 through 43 )H30 - 43
2X-RAY DIFFRACTION2chain 'H' and (resid 44 through 65 )H44 - 65
3X-RAY DIFFRACTION3chain 'H' and (resid 66 through 84 )H66 - 84
4X-RAY DIFFRACTION4chain 'H' and (resid 85 through 105 )H85 - 105
5X-RAY DIFFRACTION5chain 'H' and (resid 106 through 169 )H106 - 169
6X-RAY DIFFRACTION6chain 'H' and (resid 170 through 193 )H170 - 193
7X-RAY DIFFRACTION7chain 'H' and (resid 194 through 208 )H194 - 208
8X-RAY DIFFRACTION8chain 'H' and (resid 209 through 251 )H209 - 251
9X-RAY DIFFRACTION9chain 'H' and (resid 252 through 267 )H252 - 267
10X-RAY DIFFRACTION10chain 'H' and (resid 268 through 281 )H268 - 281
11X-RAY DIFFRACTION11chain 'L' and (resid 1 through 10 )L1 - 10
12X-RAY DIFFRACTION12chain 'L' and (resid 11 through 19 )L11 - 19
13X-RAY DIFFRACTION13chain 'L' and (resid 20 through 28 )L20 - 28
14X-RAY DIFFRACTION14chain 'I' and (resid 555 through 565 )I555 - 565

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