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- PDB-1c5o: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,... -

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Basic information

Entry
Database: PDB / ID: 1c5o
TitleSTRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
Components
  • Hirudin
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsBLOOD CLOTTING/HYDROLASE INHIBITOR / selective / S1 site inhibitor / structure-based drug design / urokinase / trypsin / thrombin / BLOOD CLOTTING-HYDROLASE INHIBITOR COMPLEX
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
BENZAMIDINE / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 1.9 Å
AuthorsKatz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L.
CitationJournal: Chem.Biol. / Year: 2000
Title: Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator.
Authors: Katz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L.
History
DepositionDec 22, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Mar 13, 2013Group: Other
Revision 1.5Jun 1, 2016Group: Source and taxonomy
Revision 1.6Oct 4, 2017Group: Advisory / Refinement description
Category: pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / software
Revision 2.0Aug 4, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / pdbx_validate_symm_contact / struct_conn / struct_conn_type / struct_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.occupancy / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _entity.formula_weight / _pdbx_entity_nonpoly.comp_id / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_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_ptnr2_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_type.id / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.1Dec 27, 2023Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Oct 16, 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
L: Thrombin light chain
H: Thrombin heavy chain
I: Hirudin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5115
Polymers35,3683
Non-polymers1432
Water7,674426
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.460, 71.820, 72.850
Angle α, β, γ (deg.)90.00, 100.90, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-478-

HOH

21H-737-

HOH

31H-742-

HOH

41H-742-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Thrombin light chain


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin


Mass: 1491.528 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Hirudo medicinalis (medicinal leech) / References: UniProt: P28504

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Protein , 1 types, 1 molecules H

#2: Protein Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin

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Non-polymers , 3 types, 428 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 426 / 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: 2.59 Å3/Da / Density % sol: 52.6 %
Crystal growMethod: vapor diffusion / pH: 7.5
Details: Thrombin was purchased from Haematologic Technologies, Inc. and acetyl-hirudin from Bachem. Thrombin was prepared as described (Skrzpczak-Jankun et al., 1991). Thrombin (1.0 mg/ml in 50 mM ...Details: Thrombin was purchased from Haematologic Technologies, Inc. and acetyl-hirudin from Bachem. Thrombin was prepared as described (Skrzpczak-Jankun et al., 1991). Thrombin (1.0 mg/ml in 50 mM HEPES, 50 % glycerol, pH 7.0) was incubated with 1.0 mM acetyl-hirudin, 10 mM benzamidine for 1 hr at 4 deg C. Glycerol was removed and the complex concentrated with a centricon 10 (Amicon) to about 10 mg/ml as determined by the Biorad protein assay kit using bovine serum albumin. Crystals of thrombin-acetyl-hirudin-benzmaidine were grown in hanging drops by vapor diffusion after streak seeding. The drops were made from 5 microliters of complex and 5 microliters of reservoir solution (0.10 M Tris, 0.50 M NaCl, 22 % (by volume) PEG 4K, pH 7.5)., VAPOR DIFFUSION
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop / Details: used seeding
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
110 mg/mlprotein1drop
20.10 MHEPES1reservoir
30.30 M1reservoirNaCl
422 %PEG5000 MME1reservoirpH7.5 or 8.2

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 7, 1999 / Details: MSC MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→38.7 Å / Num. all: 18809 / % possible obs: 51 % / Observed criterion σ(F): 0.8 / Redundancy: 1.6 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 3.8
Reflection shellResolution: 1.9→1.98 Å / Rmerge(I) obs: 0.239 / Mean I/σ(I) obs: 1.5 / % possible all: 26.4
Reflection
*PLUS
Rmerge(I) obs: 0.09

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Processing

Software
NameVersionClassification
bioteX(MSC)data collection
bioteX(MSC)data reduction
X-PLOR3.1model building
Quantamodel building
Insight IImodel building
X-PLOR3.1refinement
bioteXdata scaling
X-PLOR3.1phasing
RefinementMethod to determine structure: DIFFERENCE FOURIER PLUS REFINEMENT
Resolution: 1.9→7.5 Å / Cross valid method: X-PLOR / σ(F): 1.8
Details: Bulk solvent terms included in Fob file created with standard X-PLOR script. Arg_H126 was simultaneously refined in two conformations. No density was observed for Trp148, Thr149, Ala149A, ...Details: Bulk solvent terms included in Fob file created with standard X-PLOR script. Arg_H126 was simultaneously refined in two conformations. No density was observed for Trp148, Thr149, Ala149A, Asn149B, Val149C, Gly149D, and Lys149E in the autolysis loop, and these residues are not included in the model. Disordered waters include: HOH379, HOH380, and HOH381 which are close to one another; HOH381 IS ALSO CLOSE TO HOH711; HOH395 which is in a special position. HOH396 is close to a symmetry related equivalent of itself; HOH434 is close to a symmetry related equivalent of itself; HOH457 is close to a symmetry related equivalent of itself; (THE ABOVE WATERS HAVE STRONG DENSITY AND THEIR REFINED OCCUPANCIES ARE SIGNIFICANTLY GREATER THAN UNITY. THEY MAY REFLECT A DIFFERENT FEATURE THAN DISORDERED WATERS); HOH797 which is close to a symmetry-related equivalent of itself; HOH809 which is close to a symmetry-related equivalent of itself; HOH627 WHICH IS CLOSE TO HOH809. HIS_H57 IS MONOPROTONATED ON THE DELTA NITROGEN. HIS_H91 and His_H119 are MONOPROTONATED ON the epsilon nitrogen
RfactorNum. reflection% reflection
Rfree0.262 1437 10 %
Rwork0.2 --
obs0.2 14335 51 %
Refinement stepCycle: LAST / Resolution: 1.9→7.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2430 0 10 426 2866
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.018
X-RAY DIFFRACTIONx_angle_deg4
X-RAY DIFFRACTIONx_dihedral_angle_d25.2
X-RAY DIFFRACTIONx_improper_angle_d0.46
LS refinement shellResolution: 1.9→1.98 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.416 96 -
Rwork0.352 832 -
obs--26.2 %
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Lowest resolution: 7.5 Å / σ(F): 1.8 / % reflection Rfree: 10 % / Rfactor obs: 0.203 / Rfactor Rwork: 0.2
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_deg4
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg25.2
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.46
LS refinement shell
*PLUS
Rfactor Rfree: 0.416 / Rfactor Rwork: 0.352

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