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- PDB-5lce: Thrombin in complex with (S)-1-((R)-2-amino-3-cyclohexylpropanoyl... -

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Basic information

Entry
Database: PDB / ID: 5lce
TitleThrombin in complex with (S)-1-((R)-2-amino-3-cyclohexylpropanoyl)-N-(5-chloro-2-(hydroxymethyl)benzy l)pyrrolidine-2-carboxamide
Components
  • (Prothrombin) x 2
  • Hirudin variant-2
KeywordsHYDROLASE / COAGULATION / BLOOD CLOTTING / CONVERTION OF FIBRINOGEN TO FIBRIN / BLOOD CLOTTING INHIBITOR / THROMBIN INHIBITOR / PREORGANIZATION / GLYCOSYLATION / BLOOD
Function / homology
Function and homology information


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 ...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
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 / 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
Chem-6TH / PHOSPHATE ION / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.39 Å
AuthorsSandner, A. / Heine, A. / Klebe, G.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding.
Authors: Sandner, A. / Hufner-Wulsdorf, T. / Heine, A. / Steinmetzer, T. / Klebe, G.
History
DepositionJun 21, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2019Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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.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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_role / _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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Jan 10, 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

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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 variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,62613
Polymers35,4253
Non-polymers1,20110
Water4,882271
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-31 kcal/mol
Surface area12470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.873, 71.200, 72.636
Angle α, β, γ (deg.)90.00, 100.44, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-75-

ARG

21H-412-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

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


Mass: 4096.534 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Plasmid details: PURIFIED FROM HUMAN BLOOD PLASMA / Tissue: Blood / 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-7425.html contains sufated tyrosine
Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Prothrombin / Coagulation factor II / Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Plasmid details: PURIFIED FROM HUMAN BLOOD PLASMA / Tissue: Blood / 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 , 7 types, 280 molecules

#4: Chemical ChemComp-6TH / (2~{S})-1-[(2~{R})-2-azanyl-3-cyclohexyl-propanoyl]-~{N}-[[5-chloranyl-2-(hydroxymethyl)phenyl]methyl]pyrrolidine-2-carboxamide


Mass: 421.961 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H32ClN3O3
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#9: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#10: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 271 / 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: 2.5 Å3/Da / Density % sol: 50.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
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: ELETTRA / Beamline: 5.2R / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 11, 2016
RadiationMonochromator: a double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.36→43.39 Å / Num. obs: 73448 / % possible obs: 97.9 % / Redundancy: 2.8 % / CC1/2: 0.999 / Rsym value: 0.04 / Net I/σ(I): 12.9
Reflection shellResolution: 1.36→1.44 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.499 / Mean I/σ(I) obs: 1.6 / % possible all: 92.2

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
Cootmodel building
XDSdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1H8D

1h8d


Resolution: 1.39→43.39 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.02
RfactorNum. reflection% reflection
Rfree0.1678 3463 5 %
Rwork0.14 --
obs0.1414 69241 98.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.39→43.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2311 0 76 271 2658
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052584
X-RAY DIFFRACTIONf_angle_d0.8433508
X-RAY DIFFRACTIONf_dihedral_angle_d20.3661005
X-RAY DIFFRACTIONf_chiral_restr0.081362
X-RAY DIFFRACTIONf_plane_restr0.005462
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3899-1.40890.34011310.29032480X-RAY DIFFRACTION94
1.4089-1.42910.25881350.24782573X-RAY DIFFRACTION95
1.4291-1.45040.26041340.2142544X-RAY DIFFRACTION97
1.4504-1.47310.21731370.19262606X-RAY DIFFRACTION98
1.4731-1.49720.21121390.18322622X-RAY DIFFRACTION99
1.4972-1.5230.2371380.17052622X-RAY DIFFRACTION99
1.523-1.55070.19381390.14622642X-RAY DIFFRACTION99
1.5507-1.58060.18331380.14232623X-RAY DIFFRACTION99
1.5806-1.61280.17181390.14352646X-RAY DIFFRACTION99
1.6128-1.64790.1661390.12862645X-RAY DIFFRACTION99
1.6479-1.68620.17251390.12822645X-RAY DIFFRACTION99
1.6862-1.72840.16261400.12282644X-RAY DIFFRACTION99
1.7284-1.77510.14331390.11552644X-RAY DIFFRACTION99
1.7751-1.82740.14831390.1152645X-RAY DIFFRACTION99
1.8274-1.88640.16271390.11572642X-RAY DIFFRACTION99
1.8864-1.95380.13031400.11532652X-RAY DIFFRACTION99
1.9538-2.0320.15561400.11282678X-RAY DIFFRACTION100
2.032-2.12450.14361410.11812670X-RAY DIFFRACTION100
2.1245-2.23650.13591390.12022637X-RAY DIFFRACTION99
2.2365-2.37660.15391410.12992686X-RAY DIFFRACTION99
2.3766-2.56010.1621380.13732618X-RAY DIFFRACTION99
2.5601-2.81770.18781410.14932682X-RAY DIFFRACTION99
2.8177-3.22530.18791390.15172630X-RAY DIFFRACTION98
3.2253-4.0630.16111380.13562638X-RAY DIFFRACTION97
4.063-43.41050.16061410.15162664X-RAY DIFFRACTION97

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