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- PDB-6zuu: Crystal structure of Thrombin in complex with compound30 -

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Basic information

Entry
Database: PDB / ID: 6zuu
TitleCrystal structure of Thrombin in complex with compound30
Components
  • (ProthrombinThrombin) x 2
  • Hirudin-2
KeywordsBLOOD CLOTTING / COAGULATION / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / THROMBIN INHIBITOR / HYDROLASE
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 / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / 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 / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of platelet activation / negative regulation of astrocyte differentiation / negative regulation of cytokine production involved in inflammatory response / positive regulation of collagen biosynthetic process / 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 / regulation of cytosolic calcium ion concentration / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / negative regulation of proteolysis / 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 / Golgi lumen / positive regulation of protein localization to nucleus / 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 / 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 / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / 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-QQN / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.94 Å
AuthorsSchafer, M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics.
Authors: Hillisch, A. / Gericke, K.M. / Allerheiligen, S. / Roehrig, S. / Schaefer, M. / Tersteegen, A. / Schulz, S. / Lienau, P. / Gnoth, M. / Puetter, V. / Hillig, R.C. / Heitmeier, S.
History
DepositionJul 23, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 7, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9485
Polymers35,2973
Non-polymers6512
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3350 Å2
ΔGint-11 kcal/mol
Surface area13220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.970, 71.300, 71.860
Angle α, β, γ (deg.)90.000, 99.920, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Prothrombin / Thrombin / Coagulation factor II


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-2 / / Hirudin II


Mass: 1420.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28504

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Prothrombin / Thrombin / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / 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 , 2 types, 259 molecules

#4: Chemical ChemComp-QQN / [2-[(3-chlorophenyl)methylamino]-4-methoxy-1,3-benzoxazol-6-yl]-[(3~{R},4~{R})-3-methyl-4-oxidanyl-piperidin-1-yl]methanone


Mass: 429.897 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 258 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 50.82 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop
Details: 0.02 M phosphate buffer pH 7.5, 27% PEG 8000, 100 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54187 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Sep 30, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.939→43.187 Å / Num. obs: 23907 / % possible obs: 91 % / Redundancy: 3.4 % / Rpim(I) all: 0.071 / Rrim(I) all: 0.133 / Rsym value: 0.112 / Net I/av σ(I): 5.8 / Net I/σ(I): 8.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.939-2.033.30.581.329050.3720.690.5876.2
2.03-2.153.40.364232920.2320.4320.36491.2
2.15-2.33.40.2672.731310.170.3170.26792.1
2.3-2.493.40.2153.429440.1370.2550.21592.6
2.49-2.733.40.1634.427090.1040.1940.16393.4
2.73-3.053.40.1136.324890.0720.1350.11394.2
3.05-3.523.40.0759.222200.0480.0890.07595
3.52-4.313.40.05910.618930.0380.070.05995.9
4.31-6.093.30.05710.314880.0360.0670.05796.2
6.09-43.1873.20.05310.98360.0340.0630.05397

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.15data scaling
PHASERphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse

Resolution: 1.94→43.187 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.921 / SU B: 7.284 / SU ML: 0.107 / SU R Cruickshank DPI: 0.1553 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.155 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1221 5.1 %RANDOM
Rwork0.1637 ---
obs0.1662 22685 92.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 84.79 Å2 / Biso mean: 35.132 Å2 / Biso min: 19.58 Å2
Baniso -1Baniso -2Baniso -3
1--1.73 Å2-0 Å21.36 Å2
2--0.33 Å20 Å2
3---0.87 Å2
Refinement stepCycle: final / Resolution: 1.94→43.187 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2348 0 44 258 2650
Biso mean--43.05 42.69 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0192456
X-RAY DIFFRACTIONr_bond_other_d0.0020.022266
X-RAY DIFFRACTIONr_angle_refined_deg2.3031.9933323
X-RAY DIFFRACTIONr_angle_other_deg1.1723.0015233
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.595284
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.92223.478115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.52215429
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.31520
X-RAY DIFFRACTIONr_chiral_restr0.1380.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212678
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02512
LS refinement shellResolution: 1.94→1.989 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.308 69 -
Rwork0.267 1528 -
obs--84.81 %
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)
11.90280.52120.0821.6175-0.03352.95460.05420.00530.03470.0756-0.0955-0.1385-0.03620.1810.04140.2334-0.0505-0.12070.02910.02550.096228.81510.76412.1
21.5760.73660.06321.4849-0.04511.30490.0932-0.0897-0.06080.0463-0.07710.01340.061-0.0851-0.01610.2494-0.0251-0.13850.01270.01180.078914.377-1.18415.812
314.853-12.035-1.163810.68264.08911.3049-0.7742-1.0544-0.80730.860.59990.60290.332-0.36450.17430.6452-0.2916-0.1340.55350.30180.297217.423-2.49538.908
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1L1 - 14
2X-RAY DIFFRACTION2H16 - 1001
3X-RAY DIFFRACTION3I9 - 19

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