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- PDB-4az2: Human thrombin - inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 4az2
TitleHuman thrombin - inhibitor complex
Components
  • HIRUDIN-3A'
  • THROMBIN HEAVY CHAIN
  • THROMBIN LIGHT CHAIN
KeywordsHYDROLASE/INHIBITOR / HYDROLASE-INHIBITOR COMPLEX
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 / 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-9MU / Prothrombin / Hirudin-3A' / Hirudin-3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsBanner, D.W. / D'Arcy, A. / Winkler, F.K. / Hilpert, K.
CitationJournal: J.Med.Chem. / Year: 1994
Title: Design and Synthesis of Potent and Highly Selective Thrombin Inhibitors.
Authors: Hilpert, K. / Ackermann, J. / Banner, D.W. / Gast, A. / Gubernator, K. / Hadvary, P. / Labler, L. / Muller, K. / Schmid, G. / Tschopp, T.B.
History
DepositionJun 22, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 15, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Other
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_wavelength_list / _diffrn_source.type
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / 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_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4May 1, 2024Group: 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
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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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
D: HIRUDIN-3A'
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2105
Polymers34,4953
Non-polymers7152
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint-14.8 kcal/mol
Surface area14480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.800, 90.800, 132.500
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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Protein/peptide , 2 types, 2 molecules AD

#1: Protein/peptide THROMBIN LIGHT CHAIN / COAGULATION FACTOR II


Mass: 3489.881 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN, RESIDUES 332-361 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUDIN-3A' / HIRUDIN / HIRUDIN IIIA'


Mass: 1411.465 Da / Num. of mol.: 1 / Fragment: C-TERMINUS, RESIDUES 55-65 / Source method: obtained synthetically / Source: (synth.) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P28509, UniProt: P28508*PLUS

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Protein / Sugars , 2 types, 2 molecules B

#2: Protein THROMBIN HEAVY CHAIN / COAGULATION FACTOR II


Mass: 29594.055 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN, RESIDUES 364-620 / Source method: isolated from a natural source / Details: ASN B53 IS GLYCOSYLATED / 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


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 , 2 types, 77 molecules

#4: Chemical ChemComp-9MU / (R)-N-((S)-1-CARBAMIMIDOYL-PIPERIDIN-3-YLMETHYL)-2-(NAPHTHALENE-2-SULFONYLAMINO)-3-PHENYL-PROPIONAMIDE


Mass: 493.621 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31N5O3S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE N-TERMINAL RESIDUE IS MODIFIED IN CHAIN D. PLEASE REFER TO THE CITATION FOR FURTHER DETAILS.

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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: 4.15 Å3/Da / Density % sol: 70.4 % / Description: SOME DATA PROCESSING INFORMATION HAS BEEN LOST

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Data collection

DiffractionMean temperature: 15 K
Diffraction sourceSource: ROTATING ANODE / Type: ELLIOTT GX-21 / Wavelength: 1.5418 / Wavelength: 1.5418 Å
DetectorType: MULTIWIRE XENTRONICS / Detector: AREA DETECTOR / Date: Jan 6, 1994
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 16462 / Observed criterion σ(I): 0 / Redundancy: 2.83 % / Rmerge(I) obs: 0.05
Reflection shellResolution: 2.6→2.7 Å / % possible all: 65

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
XDSdata reduction
XDSdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN HOUSE STRUCTURES

Resolution: 2.6→17.98 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.943 / SU B: 5.893 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.276 / ESU R Free: 0.213 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS GENERATED AT RIDING POSITIONS IN REFMAC BUT NOT OUTPUT. RESIDUES B153 AND B154 HAVE ELECTRON DENSITY WHICH IS HARD TO FIT WITH THE PUBLISHED THROMBIN SEQUENCE.
RfactorNum. reflection% reflectionSelection details
Rfree0.19004 827 5.2 %RANDOM
Rwork0.14085 ---
obs0.14329 15223 90.85 %-
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 mean: 38.412 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20 Å2
2--0.12 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 2.6→17.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2424 0 49 76 2549
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.022552
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5271.9823453
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6255297
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.74423.525122
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.80715446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3311521
X-RAY DIFFRACTIONr_chiral_restr0.1010.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212030
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.601→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 36 -
Rwork0.184 651 -
obs--53.71 %

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