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- PDB-5mls: Thrombin Mutant A190S in complex with (S)-1-(D-phenylalanyl)-N-(3... -

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Basic information

Entry
Database: PDB / ID: 5mls
TitleThrombin Mutant A190S in complex with (S)-1-(D-phenylalanyl)-N-(3-chlorobenzyl)pyrrolidine-2-carboxamide
Components
  • Hirudin variant-2
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE / COAGULATION / BLOOD CLOTTING / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / PREORGANIZATION / GLYCOSILATION / BLOOD
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
D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide / D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide / PHOSPHATE ION / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsMarca, A. / Sandner, A. / Heine, A. / Klebe, G.
CitationJournal: to be published
Title: Thrombin Mutante A190S in complex with (S)-1-((R)-2-amino-3,3-diphenylpropanoyl)-N-(4-carbamimidoylbenzyl)pyrrolidine-2-carboxamide
Authors: Marca, A. / Sandner, A. / Heine, A. / Klebe, G.
History
DepositionDec 7, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 20, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 13, 2018Group: Data collection / Structure summary / Category: pdbx_molecule_features
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn / struct_conn_type
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.ptnr1_symmetry / _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.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id

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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
D: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,59914
Polymers35,4413
Non-polymers1,15811
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5070 Å2
ΔGint-34 kcal/mol
Surface area12640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.417, 71.597, 73.069
Angle α, β, γ (deg.)90.00, 100.58, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-402-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LD

#1: Protein/peptide Thrombin light chain / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Tissue: Blood / Gene: F2 / Plasmid: PT2 A190S / Details (production host): pET 21a / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-2


Mass: 1548.580 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: http://shop.bachem.com/h-7525.html contains sulfated tyrosine
Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Protein , 1 types, 1 molecules H

#2: Protein Thrombin heavy chain / Coagulation factor II


Mass: 29796.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Alanine 190 mutated to Serine / Source: (gene. exp.) Homo sapiens (human) / Tissue: Blood / Gene: F2 / Plasmid: PT2 A190S / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: P00734, thrombin

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Non-polymers , 6 types, 200 molecules

#4: Chemical ChemComp-22U / D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide / (2S)-1-[(2R)-2-amino-3-phenyl-propanoyl]-N-[(3-chlorophenyl)methyl]pyrrolidine-2-carboxamide


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 385.887 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24ClN3O2 / References: D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-NA / SODIUM ION


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


Mass: 18.015 Da / Num. of mol.: 189 / 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: 51.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 20 mM Sodium dihydrogen phosphate ph 7.5, 350 mM NaCl, 27% PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 13, 2016
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 1.62→43.7 Å / Num. obs: 44585 / % possible obs: 97.7 % / Redundancy: 3.8 % / CC1/2: 1 / Rsym value: 0.068 / Net I/σ(I): 14.3
Reflection shellResolution: 1.62→1.71 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.8 / CC1/2: 0.8 / % possible all: 95.9

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
CootPunta Carretas 0.8-premodel building
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→43.7 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.02
RfactorNum. reflection% reflection
Rfree0.18 2227 5 %
Rwork0.16 --
obs0.16 44570 97.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.62→43.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2308 0 74 189 2571
Refine LS restraintsType: f_plane_restr / Dev ideal: 0.008 / Number: 446
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62-1.65190.28761300.23182480X-RAY DIFFRACTION94
1.6519-1.69040.25481390.21282633X-RAY DIFFRACTION97
3.2332-4.0730.16281410.14182688X-RAY DIFFRACTION98
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)
10.0046-0.00090.00170.0047-0.00210.0031-0.00010.0272-0.0071-0.0126-0.0698-0.0211-0.0787-0.0468-0.00020.17930.06010.01110.12240.01440.14175.553916.135818.3132
20.0009-0.00110.00140.0017-0.00010.00260.05990.0249-0.0077-0.0118-0.00940.0044-0.006-0.06750.00040.14930.06950.01190.16-0.01220.1764-3.968713.146820.684
30.0019-0.00160.00160.0009-0.00140.0037-0.007-0.03570.00420.00640.02080.0035-0.0098-0.02570.00030.11070.04250.02870.167-0.00490.1831-1.20586.616932.8096
40.004-0.00130.00250.0018-0.00250.00180.12110.0575-0.0856-0.0462-0.09440.0696-0.0067-0.058-0.00010.17270.0434-0.05030.1638-0.02570.17970.78680.882917.5355
50.06620.01210.0740.02650.01260.08540.11110.1983-0.0019-0.1353-0.09280.00880.09750.07180.0250.24430.19170.00210.2422-0.01790.140515.46930.06858.6085
60.0183-0.00450.03210.0683-0.04970.07340.11230.158-0.0116-0.1555-0.1256-0.0230.05680.0351-0.04820.24520.2395-0.00050.288-0.0330.115315.5562-1.97648.4675
70.05720.08360.030.1490.04940.01590.14780.18540.1068-0.103-0.1813-0.14070.02370.1255-0.00230.16460.1060.03970.2380.04040.128520.69824.047815.9276
80.0248-0.0175-0.00370.01280.00170.00410.06050.0218-0.03130.0610.02790.0035-0.00850.0592-00.14240.0244-0.00280.136-0.01560.13969.49755.547332.4014
90.0631-0.0264-0.04610.0584-0.0130.04090.12570.0326-0.1841-0.0674-0.06670.13850.14410.011-0.01160.16760.0345-0.02810.127-0.01210.18639.4009-8.128527.4731
100.0645-0.0280.01520.0144-0.02150.07920.1078-0.0081-0.0512-0.0637-0.0760.07780.04990.02230.02620.15270.0318-0.00470.1204-0.0010.149710.4596-0.1527.5466
110.00440.00260.00160.00170.00180.00150.02430.00110.07920.0012-0.0336-0.0695-0.0221-0.0071-0.00010.10870.00460.04620.15740.05670.241826.17459.39623.4532
120.0002-0.001400.00830.00080.00230.02680.05680.0011-0.0263-0.0083-0.0019-0.013-0.010.01060.4690.22150.02440.4802-0.07810.155911.632-0.9905-2.6919
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'L' and (resid 1C through 7 )
2X-RAY DIFFRACTION2chain 'L' and (resid 1 through 14B )
3X-RAY DIFFRACTION3chain 'L' and (resid 14C through 14K )
4X-RAY DIFFRACTION4chain 'H' and (resid 16 through 29 )
5X-RAY DIFFRACTION5chain 'H' and (resid 30 through 50 )
6X-RAY DIFFRACTION6chain 'H' and (resid 51 through 80 )
7X-RAY DIFFRACTION7chain 'H' and (resid 81 through 125 )
8X-RAY DIFFRACTION8chain 'H' and (resid 126 through 140 )
9X-RAY DIFFRACTION9chain 'H' and (resid 141 through 197 )
10X-RAY DIFFRACTION10chain 'H' and (resid 198 through 230 )
11X-RAY DIFFRACTION11chain 'H' and (resid 231 through 244 )
12X-RAY DIFFRACTION12chain 'D' and (resid 518 through 528 )

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