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- PDB-6t8a: Thrombin in complex with diphenyl ((4-carbamimidoylphenyl)((S)-1-... -

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Basic information

Entry
Database: PDB / ID: 6t8a
TitleThrombin in complex with diphenyl ((4-carbamimidoylphenyl)((S)-1-((R)-3-cyclohexyl 2-((phenylmethyl)sulfonamido)propanoyl)pyrrolidine-2-carboxamido)methyl)phosphonate (MI-492)
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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-MUZ / PHOSPHATE ION / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.62 Å
AuthorsNgaha, S.A. / Sandner, A. / Huber, S. / Heine, A. / Steinmetzer, T. / Pilgram, O.
CitationJournal: to be published
Title: Thrombin in complex with diphenyl ((4-carbamimidoylphenyl)((S)-1-((R)-3-cyclohexyl-2-((phenylmethyl)sulfonamido)propanoyl)pyrrolidine-2-carboxamido)methyl)phosphonate (MI-492)
Authors: Ngaha, S.A. / Sandner, A. / Huber, S. / Pilgram, O. / Heine, A. / Steinmetzer, T.
History
DepositionOct 24, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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
I: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,58010
Polymers35,3683
Non-polymers1,2127
Water4,540252
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4330 Å2
ΔGint-33 kcal/mol
Surface area12410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.570, 71.302, 72.651
Angle α, β, γ (deg.)90.000, 100.610, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-75-

ARG

21H-415-

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: 1491.528 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 , 5 types, 258 molecules

#4: Chemical ChemComp-MUZ / [(~{R})-(4-carbamimidoylphenyl)-[[(2~{S})-1-[(2~{R})-3-cyclohexyl-2-[(phenylmethyl)sulfonylamino]propanoyl]pyrrolidin-2-yl]carbonylamino]methyl]-phenoxy-phosphinous acid


Mass: 693.793 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H44N5O6PS
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-PO4 / PHOSPHATE ION


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


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 252 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.87 Å3/Da / Density % sol: 57.11 %
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: 1.62→43.59 Å / Num. obs: 43325 / % possible obs: 96.2 % / Redundancy: 3.5 % / CC1/2: 0.99 / Rsym value: 0.052 / Net I/σ(I): 14.91
Reflection shellResolution: 1.62→1.72 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.43 / Num. unique obs: 6912 / CC1/2: 0.79 / Rsym value: 0.49 / % possible all: 96

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Phasing

PhasingMethod: molecular replacement

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Processing

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

1h8d


Resolution: 1.62→38.5 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.66 / Details: Phenix refinement
RfactorNum. reflection% reflection
Rfree0.1853 2167 5 %
Rwork0.1596 --
obs0.1609 43324 96.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 72.77 Å2 / Biso mean: 26.721 Å2 / Biso min: 10.66 Å2
Refinement stepCycle: final / Resolution: 1.62→38.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2302 0 77 258 2637
Biso mean--35.63 34.83 -
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 (%)
1.62-1.6570.24461400.2243264795
1.657-1.69840.24311460.2175277697
1.6984-1.74440.21311420.1976270197
1.7444-1.79570.22441470.1821280397
1.7957-1.85360.20521450.1816274497
1.8536-1.91990.21081450.1671275997
1.9199-1.99680.20661450.1565275897
1.9968-2.08760.1681450.1566274096
2.0876-2.19770.1761320.1519252589
2.1977-2.33540.16241470.1535278298
2.3354-2.51560.17681490.1544282998
2.5156-2.76870.19791460.1691278898
2.7687-3.16920.19521480.1666279798
3.1692-3.99220.18981420.1431271394
3.99-38.50.15661480.1484279595
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)
14.64010.02091.29167.0709-0.54212.04550.28160.0544-0.3073-0.0135-0.14180.44980.1151-0.2103-0.13750.13720.0283-0.01940.1693-0.03880.13940.73470.991117.4317
22.6798-0.6602-0.96231.2911.46923.63740.31720.7334-0.1947-0.4955-0.446-0.06670.32960.22220.02530.29980.15850.00720.3519-0.01950.182415.32770.0068.7117
30.9427-1.3619-0.20933.88251.05482.11650.32640.34820.0351-0.2996-0.2743-0.25540.32770.2249-0.08010.23310.1270.00190.3003-0.00980.203223.5162-5.898614.2774
41.4805-0.7350.48751.1127-0.23381.33170.32510.445-0.0158-0.3137-0.2931-0.13280.22270.3571-0.0410.24480.11280.01860.2798-0.00880.176818.2401-0.56411.5365
51.9053-0.8061-1.13481.38020.71760.80410.13270.35610.3376-0.1851-0.2063-0.2455-0.01780.2461-0.03080.16590.07110.04820.22550.05290.17114.318611.316713.172
62.6206-0.7908-0.83383.47660.17354.7281-0.0154-0.37140.11810.36030.0244-0.0867-0.05140.11390.01410.12820.03520.00220.1489-0.01460.15199.49795.817232.4898
71.4875-1.2430.69831.8364-1.05341.48040.1083-0.0291-0.2546-0.1010.00770.2860.2397-0.0589-0.09270.18870.0076-0.00090.1328-0.0040.19289.0464-7.861427.2413
81.6632-1.13050.18344.1946-0.2141.50370.0918-0.0598-0.1121-0.0639-0.05080.10120.14430.0172-0.04140.12780.02160.00130.1575-0.00480.125210.4312-0.153327.3798
96.43973.0607-5.59848.282-3.77989.05040.2223-0.15450.6318-0.1749-0.1422-0.5499-0.38150.8539-0.09570.16030.00320.04640.24210.0070.365426.36079.580123.0362
107.00142.37247.29897.24462.46579.7101-0.09740.41380.1588-0.1202-0.0092-0.1658-0.38660.21240.13390.19010.05650.03760.13630.01170.1454.960315.643518.3159
114.02121.6428-1.06333.7457-3.95084.45310.15290.08930.117-0.03040.03930.4501-0.1263-0.2833-0.23890.1470.07090.00120.2057-0.0250.1747-3.76813.142821.0546
124.15362.67541.74984.0855-0.33012.18110.0931-0.48120.03330.3345-0.00230.1784-0.0743-0.1989-0.040.15360.04780.07150.2039-0.00870.2132-1.28276.681332.4991
130.24250.10790.46081.38880.85931.20410.26830.726-0.0528-0.69970.0216-0.2772-0.09660.10820.06670.80180.36890.08340.7049-0.16530.054811.9361-0.0689-3.1099
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 129 )H85 - 129
5X-RAY DIFFRACTION5chain 'H' and (resid 130 through 151 )H130 - 151
6X-RAY DIFFRACTION6chain 'H' and (resid 152 through 169 )H152 - 169
7X-RAY DIFFRACTION7chain 'H' and (resid 170 through 231 )H170 - 231
8X-RAY DIFFRACTION8chain 'H' and (resid 232 through 267 )H232 - 267
9X-RAY DIFFRACTION9chain 'H' and (resid 268 through 281 )H268 - 281
10X-RAY DIFFRACTION10chain 'L' and (resid 1 through 10 )L1 - 10
11X-RAY DIFFRACTION11chain 'L' and (resid 11 through 19 )L11 - 19
12X-RAY DIFFRACTION12chain 'L' and (resid 20 through 28 )L20 - 28
13X-RAY DIFFRACTION13chain 'I' and (resid 555 through 565 )I555 - 565

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