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- PDB-3uwj: Human Thrombin In Complex With MI353 -

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Basic information

Entry
Database: PDB / ID: 3uwj
TitleHuman Thrombin In Complex With MI353
Components
  • Hirudin variant-2
  • Thrombin Heavy Chain
  • Thrombin Light Chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Serine Protease / Kringle / Hydrolase / Blood Coagulation / Blood Clotting / Convertion Of Fibrinogen To Fibrin / Cleavage On Pairs Of Basic Residues / Hirudin / Glycosylation / Blood / HYDROLASE-HYDROLASE INHIBITOR complex
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
N-(BENZYLSULFONYL)-D-LEUCYL-N-(4-CARBAMIMIDOYLBENZYL)-L-PROLINAMIDE / PHOSPHATE ION / Chem-TIF / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsBiela, A. / Heine, A. / Klebe, G.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Ligand binding stepwise disrupts water network in thrombin: enthalpic and entropic changes reveal classical hydrophobic effect
Authors: Biela, A. / Sielaff, F. / Terwesten, F. / Heine, A. / Steinmetzer, T. / Klebe, G.
History
DepositionDec 2, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 12, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2016Group: Database references
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / 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 / _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 1.3Nov 8, 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 1.4Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Thrombin Light Chain
H: Thrombin Heavy Chain
I: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9299
Polymers35,5393
Non-polymers1,3896
Water6,287349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4010 Å2
ΔGint-35 kcal/mol
Surface area12850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.300, 71.200, 72.400
Angle α, β, γ (deg.)90.00, 100.70, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-1062-

HOH

21H-1267-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Thrombin Light Chain


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


Mass: 1662.683 Da / Num. of mol.: 1 / Fragment: residues in UNP 60-72 / Source method: obtained synthetically / Details: Synthetic Fragment of Hirudo Medicinalis / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Thrombin Heavy Chain


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#4: 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, 354 molecules

#5: Chemical ChemComp-TIF / N-(benzylsulfonyl)-D-leucyl-N-(4-carbamimidoylbenzyl)-L-prolinamide


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 513.652 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H35N5O4S
References: N-(BENZYLSULFONYL)-D-LEUCYL-N-(4-CARBAMIMIDOYLBENZYL)-L-PROLINAMIDE
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-NA / SODIUM ION


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


Mass: 18.015 Da / Num. of mol.: 349 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.5 Å3/Da / Density % sol: 50.9 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 15% PEG 8000, 20mM sodium phosphate, 175mM sodium chloride, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.91841 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Jun 25, 2010 / Details: Collimating Mirror
RadiationMonochromator: Double Crystal Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. all: 55148 / Num. obs: 55148 / % possible obs: 97.3 % / Redundancy: 2.7 % / Biso Wilson estimate: 13.66 Å2 / Rsym value: 0.053 / Net I/σ(I): 17.7
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 2.6 % / Mean I/σ(I) obs: 1.9 / Num. unique all: 2816 / Rsym value: 0.468 / % possible all: 98.5

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7_650)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H8D

1h8d


Resolution: 1.5→22.496 Å / Occupancy max: 1 / Occupancy min: 0.19 / FOM work R set: 0.8976 / SU ML: 0.19 / Cross valid method: Free R / σ(F): 0 / Phase error: 17.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1828 2635 5.07 %Random
Rwork0.1601 ---
all0.1613 54651 --
obs0.1613 52016 92.72 %-
Solvent computationShrinkage radii: 0.72 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 59.119 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 100.19 Å2 / Biso mean: 22.1079 Å2 / Biso min: 6.52 Å2
Baniso -1Baniso -2Baniso -3
1-1.3047 Å20 Å2-3.2169 Å2
2---1.9783 Å2-0 Å2
3---0.6735 Å2
Refinement stepCycle: LAST / Resolution: 1.5→22.496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2341 0 68 349 2758
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0182574
X-RAY DIFFRACTIONf_angle_d1.0953499
X-RAY DIFFRACTIONf_dihedral_angle_d16.8851019
X-RAY DIFFRACTIONf_chiral_restr0.074366
X-RAY DIFFRACTIONf_plane_restr0.005443
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5-1.52730.27781140.2629235584
1.5273-1.55660.25481280.2286242987
1.5566-1.58840.21031150.2095247489
1.5884-1.62290.2131710.1987251191
1.6229-1.66070.1851200.1839254891
1.6607-1.70220.21281550.1789250891
1.7022-1.74820.19841330.1734259492
1.7482-1.79960.2281480.1601262594
1.7996-1.85770.19561350.1569266294
1.8577-1.9240.19841300.1594262494
1.924-2.0010.17791430.1535264795
2.001-2.0920.18671320.152268596
2.092-2.20220.16551340.1486268896
2.2022-2.34010.18171450.1587267495
2.3401-2.52060.17711480.1542270496
2.5206-2.77380.19461550.1691267195
2.7738-3.17420.19351570.1614267295
3.1742-3.99550.1641230.1393267294
3.9955-22.49840.14881490.1491263892
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)
10.3559-0.2204-0.19650.45010.16780.42520.26220.2747-0.2804-0.1951-0.13460.12050.194-0.01160.19960.15830.0852-0.04230.166-0.0690.12198.1912-2.739311.3984
20.2519-0.23750.21620.4817-0.19190.26430.25040.43130.0088-0.275-0.2554-0.12020.12070.1977-0.08250.16220.1206-0.00050.2244-0.02590.087816.2362-1.08978.7928
30.39780.40790.00980.54370.26860.69680.21540.22720.00820.0086-0.0405-0.1990.05890.23680.33420.08210.06360.0280.19280.02810.116125.7574-0.961816.6078
40.4249-0.3484-0.06930.28810.02050.09290.03180.04450.03780.0002-0.0264-0.0328-0.03370.0146-0.0030.10990.0306-0.00920.0914-0.01140.08099.36895.972123.3798
50.587-0.36330.25370.2362-0.18850.36780.03040.0098-0.2680.0458-0.01150.26370.1602-0.0157-0.08430.12410.0133-0.02390.06390.00450.11267.9295-9.545826.887
60.4902-0.11990.15730.1565-0.0530.33770.0401-0.0568-0.140.03660.00640.05820.0809-0.00780.0030.10340.01680.00140.08180.00260.108510.6306-4.08628.0656
70.82860.6844-1.38891.0063-1.18252.41110.0796-0.04020.25170.043-0.012-0.1727-0.28960.1844-0.03680.1467-0.02410.01930.15650.00660.253326.87788.878821.978
80.0037-0.0231-0.01090.17470.08230.03970.07740.10080.007-0.15020.0265-0.0512-0.10730.03360.09360.40920.19110.0410.5288-0.1130.101412.0755-1.5468-3.5295
90.3329-0.40650.15260.9271-0.22050.40360.0110.05970.1129-0.1042-0.125-0.1093-0.2332-0.05120.02950.15390.05620.00510.12160.00240.11512.87515.31518.2363
101.0303-0.005500.0703-0.01560.06080.0187-0.0357-0.1069-0.0417-0.0680.0349-0.0168-0.13450.02960.10810.04260.00340.1737-0.00730.119-4.8887.533422.7639
110.08220.11470.08520.22790.02240.36010.0596-0.0694-0.00140.00610.09180.0027-0.0578-0.1824-0.05350.13250.03620.05260.16370.00150.1459-1.27975.157333.1978
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain H and resid 16:41)H16 - 41
2X-RAY DIFFRACTION2(chain H and resid 42:83)H42 - 83
3X-RAY DIFFRACTION3(chain H and resid 84:111)H84 - 111
4X-RAY DIFFRACTION4(chain H and resid 112:144)H112 - 144
5X-RAY DIFFRACTION5(chain H and resid 145:173)H145 - 173
6X-RAY DIFFRACTION6(chain H and resid 174:232)H174 - 232
7X-RAY DIFFRACTION7(chain H and resid 233:246)H233 - 246
8X-RAY DIFFRACTION8(chain I and resid 55:65)I55 - 65
9X-RAY DIFFRACTION9(chain L and resid 1C:11)L1
10X-RAY DIFFRACTION10(chain L and resid 12:14C)L12 - 14
11X-RAY DIFFRACTION11(chain L and resid 14D:14K)L14

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