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- PDB-4loy: Crystal Structure Analysis of thrombin in complex with compound D... -

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Basic information

Entry
Database: PDB / ID: 4loy
TitleCrystal Structure Analysis of thrombin in complex with compound D57, 5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2- oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1- yl)-3-oxopropyl]amide (SAR107375)
Components
  • Hirudin variant-2
  • Thrombin heavy chain
  • Thrombin light chain
Keywordshydrolase/hydrolase inhibitor / serine proteases / dual thrombin/factor Xa inhibition / hydrolase-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-6XS / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.77 Å
AuthorsStehlin-Gaon, C. / Bocskei, Z.
CitationJournal: J.Med.Chem. / Year: 2013
Title: 5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally ...Title: 5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor.
Authors: Meneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J.M. / Petit, F. / Bocskei, Z. / Schreuder, H. / Alet, N. / Herault, J.P. / Millet, L. / ...Authors: Meneyrol, J. / Follmann, M. / Lassalle, G. / Wehner, V. / Barre, G. / Rousseaux, T. / Altenburger, J.M. / Petit, F. / Bocskei, Z. / Schreuder, H. / Alet, N. / Herault, J.P. / Millet, L. / Dol, F. / Florian, P. / Schaeffer, P. / Sadoun, F. / Klieber, S. / Briot, C. / Bono, F. / Herbert, J.M.
History
DepositionJul 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 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_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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_atom_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_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Thrombin heavy chain
I: Hirudin variant-2
L: Thrombin light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0347
Polymers34,1463
Non-polymers8884
Water5,296294
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3820 Å2
ΔGint-30 kcal/mol
Surface area13020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.522, 71.196, 73.140
Angle α, β, γ (deg.)90.000, 100.910, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-471-

HOH

21H-588-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules IL

#2: Protein/peptide Hirudin variant-2


Mass: 1363.399 Da / Num. of mol.: 1 / Fragment: unp residues 62-71 / Source method: isolated from a natural source / Source: (natural) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945
#3: Protein/peptide Thrombin light chain / Thrombin light chain


Mass: 3188.627 Da / Num. of mol.: 1 / Fragment: unp residues 334-360 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P00734, thrombin

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Protein / Sugars , 2 types, 2 molecules H

#1: Protein Thrombin heavy chain / Thrombin heavy chain


Mass: 29594.055 Da / Num. of mol.: 1 / Fragment: unp residues 364-620 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


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 , 3 types, 297 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-6XS / 5-Chloro-thiophene-2-carboxylic acid [(S)-2-[2-chloro-5-fluoro-3-(2-oxo-piperidin-1-yl)-benzenesulfonylamino]-3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-amide


Mass: 620.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28Cl2FN5O5S2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / 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: 2.64 Å3/Da / Density % sol: 53.41 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 0.1 M SODIUM PHASPHATE PH=7.3, 20% PEG8000, 5MG/ML THROMBIN, 0.2 M NACL, 1 mM INHIBNITOR, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 30, 2007 / Details: Osmic blue mirrors
RadiationMonochromator: Osmic blue mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.77→50 Å / Num. all: 23272 / Num. obs: 23272 / % possible obs: 66.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 1.7 % / Rmerge(I) obs: 0.024 / Χ2: 0.868 / Net I/σ(I): 32.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.77-1.831.10.0866301.012118.2
1.83-1.911.20.0689660.881127.9
1.91-1.991.30.04913201.006138.1
1.99-2.11.50.04128670.959182.6
2.1-2.231.70.03630620.925188.2
2.23-2.41.80.03122410.967164.7
2.4-2.641.80.02734240.791198.1
2.64-3.031.90.02533780.8197.4
3.03-3.811.90.02325350.813172.2
3.81-5020.0228490.888180.1

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
HKL-2000data reduction
BUSTER2.11.5refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.77→19.58 Å / Cor.coef. Fo:Fc: 0.9482 / Cor.coef. Fo:Fc free: 0.935 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.165 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2078 1198 5.15 %RANDOM
Rwork0.1766 ---
all0.1782 23241 --
obs0.1782 23241 67.03 %-
Displacement parametersBiso max: 138.08 Å2 / Biso mean: 30.424 Å2 / Biso min: 11.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.1773 Å20 Å20.1913 Å2
2---0.6066 Å20 Å2
3---0.4293 Å2
Refine analyzeLuzzati coordinate error obs: 0.206 Å
Refinement stepCycle: LAST / Resolution: 1.77→19.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2344 0 55 294 2693
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d879SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes346HARMONIC5
X-RAY DIFFRACTIONt_it2461HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion299SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2982SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2461HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3332HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.76
X-RAY DIFFRACTIONt_other_torsion15.72
LS refinement shellResolution: 1.77→1.85 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.3055 43 4.88 %
Rwork0.1934 838 -
all0.1988 881 -
obs--67.03 %
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)
11.37120.67260.05731.18250.10281.12040.1163-0.0911-0.05870.0679-0.08250.01710.0699-0.0728-0.0339-0.0544-0.0255-0.0124-0.07030.0126-0.051914.3376-1.147215.9808
20.20671.1260.40910.56810.13710.52150.01230.0193-0.00430.0228-0.0336-0.0132-0.03010.02890.02130-0.02060.0066-0.0104-0.0020.012529.014210.433211.5629
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ H|* }H16 - 301
2X-RAY DIFFRACTION2{ L|* }L1 - 14

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