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- PDB-4hfp: Structure of thrombin mutant S195a bound to the active site inhib... -

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Basic information

Entry
Database: PDB / ID: 4hfp
TitleStructure of thrombin mutant S195a bound to the active site inhibitor argatroban
Components(Prothrombin) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Serine protease / prethrombin-2 / autoactivation / hydrolase / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin ...cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / 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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / regulation of cytosolic calcium ion concentration / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of proteolysis / negative regulation of cytokine production involved in inflammatory response / Peptide ligand-binding receptors / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / lipopolysaccharide binding / 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 / regulation of cell shape / heparin binding / : / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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
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 / 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
S-argatroban / Chem-15U / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsPozzi, N. / Chen, Z. / Zapata, F. / Lin, W. / Barranco-Medina, S. / Pelc, L.A. / Di Cera, E.
CitationJournal: J.Biol.Chem. / Year: 2013
Title: Autoactivation of thrombin precursors.
Authors: Pozzi, N. / Chen, Z. / Zapata, F. / Niu, W. / Barranco-Medina, S. / Pelc, L.A. / Di Cera, E.
History
DepositionOct 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2013Group: Other
Revision 1.2May 22, 2013Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_PDB_ins_code / _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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 27, 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
A: Prothrombin
B: Prothrombin
C: Prothrombin
D: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8868
Polymers66,8234
Non-polymers1,0634
Water1,18966
1
A: Prothrombin
B: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9434
Polymers33,4112
Non-polymers5322
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint-20 kcal/mol
Surface area13370 Å2
MethodPISA
2
C: Prothrombin
D: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9434
Polymers33,4112
Non-polymers5322
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-20 kcal/mol
Surface area13590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.229, 77.229, 94.875
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein/peptide Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 3647.075 Da / Num. of mol.: 2 / Mutation: S195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#2: Protein Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 29764.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-15U / (2R,4R)-4-methyl-1-(N~2~-{[(3S)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}-L-arginyl)piperidine-2-carboxylic acid / S-argatroban


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 508.634 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H36N6O5S / References: S-argatroban
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / Source method: isolated from a natural source / Formula: H2O
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: 2.12 Å3/Da / Density % sol: 41.9 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 100mM Na acetate pH 4.6 and 25% PEG 8000, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 26, 2012
RadiationMonochromator: Mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
111.000H, 1.000K, L10.524
11-1.000H, 1.000K, -L20.476
ReflectionResolution: 2.4→40.42 Å / Num. all: 21851 / Num. obs: 21611 / % possible obs: 98.9 % / Observed criterion σ(F): -0.2 / Observed criterion σ(I): -0.2 / Redundancy: 6.3 % / Rmerge(I) obs: 0.107 / Net I/σ(I): 13.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
2.4-2.443.10.3622.8990191.5
2.44-2.493.80.3653.21069197.7
2.49-2.5340.3533.41049198.3
2.53-2.594.20.3413.71083198.7
2.59-2.644.30.32241064198.6
2.64-2.74.50.3114.31088198.6

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPfrom ccp4phasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1SHH

1shh


Resolution: 2.4→40.42 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.876 / SU B: 19.689 / SU ML: 0.208 / Cross valid method: THROUGHOUT / ESU R: 0.164 / ESU R Free: 0.06 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23805 1105 5.1 %RANDOM
Rwork0.167 ---
obs0.17049 20437 98.57 %-
all-20733 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 55.751 Å2
Baniso -1Baniso -2Baniso -3
1-3.77 Å20 Å20 Å2
2--3.77 Å20 Å2
3----7.54 Å2
Refinement stepCycle: LAST / Resolution: 2.4→40.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4637 0 72 66 4775
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0224833
X-RAY DIFFRACTIONr_angle_refined_deg0.9941.9746537
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1695569
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.84823.363226
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.23115850
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4251540
X-RAY DIFFRACTIONr_chiral_restr0.0660.2677
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0213666
X-RAY DIFFRACTIONr_mcbond_it0.1411.52845
X-RAY DIFFRACTIONr_mcangle_it0.25824587
X-RAY DIFFRACTIONr_scbond_it0.40131988
X-RAY DIFFRACTIONr_scangle_it0.6364.51950
LS refinement shellResolution: 2.399→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 84 -
Rwork0.189 1364 -
obs-1364 91.3 %
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)
16.19261.3092-2.77663.86862.93818.2448-0.22920.14320.0706-0.44240.3268-0.7999-0.48640.1544-0.09770.1441-0.07650.05130.1059-0.08170.380137.595310.5674-2.8221
20.85320.1506-3.9802-1.2948-1.585110.8349-0.0172-0.2361-0.349-0.08450.021-0.13890.1165-0.0992-0.00380.02820.0114-0.17090.61470.25430.788129.9799-1.5382.5553
31.750.5407-1.16010.685-1.33692.36050.06750.18430.10970.0406-0.11350.0321-0.14130.04970.04590.1878-0.0306-0.05550.2382-0.08760.318821.986518.87674.4834
43.07551.86742.42171.33450.43492.90960.1714-0.00580.13020.1608-0.06620.1961-0.12840.108-0.10520.2488-0.01710.02950.0624-0.04120.264920.591722.366-6.2689
50.98770.45740.32880.9082-0.03210.2355-0.1586-0.43720.50440.02730.07560.0395-0.2763-0.17620.08310.3470.07010.04530.3511-0.12850.435520.035827.48230.8671
62.1884-0.27170.09271.62880.731.6158-0.12270.0949-0.0556-0.31260.1249-0.0831-0.2280.0875-0.00220.1801-0.03040.01870.13430.02670.182220.295119.5438-11.3975
70.87980.446-0.27510.511-0.40280.2132-0.04340.11230.05220.00390.04040.1343-0.0212-0.04380.0030.07370.01370.00240.0945-0.02480.228319.16775.6884-1.1233
82.1126-0.2349-1.09891.24390.17940.7593-0.0418-0.0108-0.013-0.10690.08680.0374-0.1581-0.153-0.0450.14720.05870.01550.13260.04210.167310.16576.871-1.1708
93.88050.8432-0.09932.47880.68222.0151-0.177-0.0872-0.36930.1799-0.0273-0.20120.1410.08410.20430.10450.00310.01050.07550.02330.113319.85454.3804-0.4517
101.279-1.20591.10552.8287-0.3150.9944-0.05740.20690.2014-0.3412-0.0721-0.1459-0.17290.20290.12950.1437-0.01950.00140.1019-0.01560.175417.288211.149-10.1083
119.210511.9551-2.567814.1278-0.9081.01540.2837-0.93170.44440.1549-0.30240.1753-0.45250.61120.01870.27280.0630.01250.3844-0.08130.377248.718-1.1094-1.5063
128.22847.73350.15867.1339-0.15694.277-0.41210.35490.7511-0.43140.26810.8332-0.0482-0.12360.1440.22030.0496-0.00730.1872-0.01050.427939.5606-5.4582-10.8275
132.0046-0.5169-2.89654.52693.75734.9252-0.10430.04050.2549-0.26490.3650.0512-0.07760.2164-0.26070.16220.0103-0.01380.22910.02840.258952.248-11.2191-12.0067
141.6074-0.21311.31530.81970.35890.92460.21630.1689-0.1401-0.11190.0725-0.4170.08930.1084-0.28870.30930.01730.00220.21590.00960.463662.3532-17.9916-0.0374
153.40670.41081.14182.1295-0.78120.3980.17350.0773-0.45820.3914-0.2871-0.7139-0.07340.21770.11350.40070.01380.05510.34280.00910.49764.9966-23.0288-0.7565
160.94810.51891.1761.61881.70143.92070.39190.10120.03460.3839-0.0027-0.23690.050.2618-0.38920.36470.07810.02190.24080.00610.435861.1464-19.71891.2757
172.05140.15290.26622.06090.95012.0039-0.0054-0.27890.02290.11670.0152-0.01450.09650.1114-0.00980.1710.01310.03950.14630.00660.217150.4164-12.9971-0.0451
182.27220.97970.49431.683-0.06172.6709-0.0726-0.0627-0.5044-0.1696-0.084-0.21450.35830.07660.15660.19120.0767-0.03160.13660.00940.353445.6227-26.9243-9.4255
191.81650.86380.26922.17720.21360.58540.12540.107-0.0285-0.2093-0.0398-0.13-0.0174-0.0902-0.08560.12080.02820.01180.1647-0.00820.18244.9381-20.4975-7.2349
207.2547.44676.81959.78016.11036.41820.2965-0.406-0.08160.5179-0.0606-0.27370.1552-0.1115-0.23590.2155-0.06020.01880.6032-0.08470.336249.6099-17.728312.993
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 10
2X-RAY DIFFRACTION2A11 - 14
3X-RAY DIFFRACTION3B16 - 38
4X-RAY DIFFRACTION4B39 - 59
5X-RAY DIFFRACTION5B60 - 85
6X-RAY DIFFRACTION6B86 - 127
7X-RAY DIFFRACTION7B128 - 146
8X-RAY DIFFRACTION8B147 - 185
9X-RAY DIFFRACTION9B186 - 205
10X-RAY DIFFRACTION10B206 - 245
11X-RAY DIFFRACTION11C1 - 8
12X-RAY DIFFRACTION12C9 - 14
13X-RAY DIFFRACTION13D16 - 30
14X-RAY DIFFRACTION14D31 - 59
15X-RAY DIFFRACTION15D60 - 72
16X-RAY DIFFRACTION16D73 - 100
17X-RAY DIFFRACTION17D101 - 145
18X-RAY DIFFRACTION18D146 - 185
19X-RAY DIFFRACTION19D186 - 229
20X-RAY DIFFRACTION20D230 - 245

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