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- PDB-3b23: Crystal structure of thrombin-variegin complex: Insights of a nov... -

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Basic information

Entry
Database: PDB / ID: 3b23
TitleCrystal structure of thrombin-variegin complex: Insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
Components
  • Thrombin heavy chain
  • Thrombin light chain
  • Variegin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


molecular function inhibitor activity / positive regulation of lipid kinase activity / 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 / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway ...molecular function inhibitor activity / positive regulation of lipid kinase activity / 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 / 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 / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / positive regulation of cell population proliferation / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. ...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 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
Prothrombin / Variegin
Similarity search - Component
Biological speciesHomo sapiens (human)
Amblyomma variegatum (tropical bont tick)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsKoh, C.Y. / Kumar, S. / Swaminathan, K. / Kini, R.M.
CitationJournal: Plos One / Year: 2011
Title: Crystal structure of thrombin in complex with s-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
Authors: Koh, C.Y. / Kumar, S. / Kazimirova, M. / Nuttall, P.A. / Radhakrishnan, U.P. / Kim, S. / Jagadeeswaran, P. / Imamura, T. / Mizuguchi, J. / Iwanaga, S. / Swaminathan, K. / Kini, R.M.
History
DepositionJul 20, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 23, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: 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
A: Thrombin light chain
B: Thrombin heavy chain
C: Variegin


Theoretical massNumber of molelcules
Total (without water)37,4893
Polymers37,4893
Non-polymers00
Water91951
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3960 Å2
ΔGint-10 kcal/mol
Surface area14300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.658, 50.826, 61.535
Angle α, β, γ (deg.)90.00, 98.70, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide Thrombin light chain / alpha-thrombin / light chain


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: pCAGG/mdhfr/prethrombin-2
Cell line (production host): SP2/0 Ag14 mouse myeloma cells (ATCC CRL-1581)
Production host: Mus musculus (house mouse) / References: UniProt: P00734, thrombin
#2: Protein Thrombin heavy chain / alpha-thrombin / heavy chain


Mass: 29780.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Plasmid: pCAGG/mdhfr/prethrombin-2
Cell line (production host): SP2/0 Ag14 mouse myeloma cells (ATCC CRL-1581)
Production host: Mus musculus (house mouse) / References: UniProt: P00734, thrombin
#3: Protein/peptide Variegin


Mass: 3611.825 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Peptide is chemically synthesized based on sequence of a thrombin inhibitor found in the salivary gland extract of Amblyomma variegatum
Source: (synth.) Amblyomma variegatum (tropical bont tick) / References: UniProt: P85800
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 51 / Source method: isolated from a natural source / Formula: H2O

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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: 2.57 Å3/Da / Density % sol: 52.14 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 100mM HEPES buffer pH 7.4, 20-25% (w/v) PEG 8000, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 28, 2007
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 15137 / % possible obs: 98.1 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 20
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.154 / Mean I/σ(I) obs: 5.4 / % possible all: 97

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1ABI

1abi


Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.923 / SU B: 19.862 / SU ML: 0.208 / Isotropic thermal model: Isotropic & TLS / Cross valid method: THROUGHOUT / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25944 724 5.2 %RANDOM
Rwork0.20787 ---
obs0.21049 13298 92.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 57.826 Å2
Baniso -1Baniso -2Baniso -3
1--1.05 Å20 Å2-4.79 Å2
2--2.49 Å20 Å2
3----2.88 Å2
Refinement stepCycle: LAST / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2464 0 0 51 2515
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222534
X-RAY DIFFRACTIONr_bond_other_d0.0010.021793
X-RAY DIFFRACTIONr_angle_refined_deg1.2241.9583427
X-RAY DIFFRACTIONr_angle_other_deg0.81134343
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8185302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.42623.471121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.32715444
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2291520
X-RAY DIFFRACTIONr_chiral_restr0.0730.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212786
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02529
X-RAY DIFFRACTIONr_mcbond_it0.491.51516
X-RAY DIFFRACTIONr_mcbond_other0.0781.5613
X-RAY DIFFRACTIONr_mcangle_it0.93122447
X-RAY DIFFRACTIONr_scbond_it1.19131018
X-RAY DIFFRACTIONr_scangle_it1.9364.5980
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 44 -
Rwork0.276 659 -
obs--63.79 %
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)
17.7683-5.39544.30747.535-4.21337.22610.61510.1421-0.4183-0.3334-0.26570.58260.9106-0.379-0.34940.2998-0.1234-0.1240.1748-0.04980.20814.0794-16.84688.3862
23.0952-0.15131.95262.2568-0.40624.9670.15320.37640.16390.1246-0.2425-0.14380.07030.8190.08920.0587-0.029-0.0150.18840.04460.055820.3728-8.373814.5645
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 14
2X-RAY DIFFRACTION2B16 - 247

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