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- PDB-1ca8: Thrombin inhibitors with rigid tripeptidyl aldehydes -

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Basic information

Entry
Database: PDB / ID: 1ca8
TitleThrombin inhibitors with rigid tripeptidyl aldehydes
Components
  • HIRUGEN
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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 / 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 / regulation of cell shape / heparin binding / Thrombin signalling through proteinase activated receptors (PARs) / : / toxin activity / 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
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
2-{(3S)-3-[(benzylsulfonyl)amino]-2-oxopiperidin-1-yl}-N-{(2S)-1-[(3S)-1-carbamimidoylpiperidin-3-yl]-3-oxopropan-2-yl}acetamide / Chem-0KV / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHirudo medicinalis (medicinal leech)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsKrishnan, R. / Zhang, E. / Hakansson, K. / Arni, R.K. / Tulinsky, A. / Lim-Wilby, M.S.L. / Levy, O.E. / Semple, J.E. / Brunck, T.K.
CitationJournal: Biochemistry / Year: 1998
Title: Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes
Authors: Krishnan, R. / Zhang, E. / Hakansson, K. / Arni, R.K. / Tulinsky, A. / Lim-Wilby, M.S. / Levy, O.E. / Semple, J.E. / Brunck, T.K.
History
DepositionApr 27, 1998Processing site: BNL
Revision 1.0Apr 27, 1999Provider: repository / Type: Initial release
Revision 1.1Mar 24, 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 1.3Jul 27, 2011Group: Database references
Revision 1.4Dec 12, 2012Group: Other
Revision 1.5Aug 9, 2023Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description
Category: database_2 / pdbx_database_status ...database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.process_site / _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_leaving_atom_flag / _struct_conn.pdbx_ptnr2_PDB_ins_code / _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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification
Remark 650 HELIX DETERMINATION METHOD: TAKEN FROM RELEASED PDB ENTRY 1AY6
Remark 700 SHEET DETERMINATION METHOD: TAKEN FROM RELEASED PDB ENTRY 1AY6

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thrombin light chain
B: Thrombin heavy chain
C: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9916
Polymers35,4383
Non-polymers5533
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.130, 72.120, 73.140
Angle α, β, γ (deg.)90.00, 100.80, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 2 types, 2 molecules AC

#1: Protein/peptide Thrombin light chain


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: Peptidase S1 domain / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: BLOOD / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUGEN


Mass: 1561.577 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / References: UniProt: P01050*PLUS

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Protein , 1 types, 1 molecules B

#2: Protein Thrombin heavy chain


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

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Non-polymers , 3 types, 137 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-0KV / 2-{(3S)-3-[(benzylsulfonyl)amino]-2-oxopiperidin-1-yl}-N-{(2S)-1-[(3S)-1-carbamimidoylpiperidin-3-yl]-3-oxopropan-2-yl}acetamide / CVS1695


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 506.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H34N6O5S
References: 2-{(3S)-3-[(benzylsulfonyl)amino]-2-oxopiperidin-1-yl}-N-{(2S)-1-[(3S)-1-carbamimidoylpiperidin-3-yl]-3-oxopropan-2-yl}acetamide
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Nonpolymer detailsTHE ACTIVE SITE INHIBITOR IS IN ITS S CHIRAL FORM. THE ACTIVE SITE SER 195 IS CLOSE TO THE CARBONYL ...THE ACTIVE SITE INHIBITOR IS IN ITS S CHIRAL FORM. THE ACTIVE SITE SER 195 IS CLOSE TO THE CARBONYL CARBON (C3) OF THE ALDEHYDE GROUP OF THE INHIBITOR BUT DOES NOT FORM A TETRAHEDRAL INTERMEDIATE

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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 %
Crystal growpH: 7.5
Details: CRYSTALLIZED FROM 25% PEG 8K, 0.1M SOD, PHOSPHATE BUFFER PH 7.5, MACROSEEDED TO MAKE LARGER CRYSTALS
Crystal
*PLUS
Crystal grow
*PLUS
Method: unknown
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
128 %PEG800011
20.1 MTris11
30.2 Msodium acetate11
41 mM11NaN3
515 mMprotain12

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Data collection

DiffractionMean temperature: 300 K
Diffraction sourceWavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Aug 1, 1995
RadiationMonochromator: NI FILTER / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionHighest resolution: 1.8 Å / Num. obs: 18157 / % possible obs: 61 % / Observed criterion σ(I): 2.5 / Redundancy: 2 % / Rmerge(I) obs: 0.052 / Rsym value: 0.12 / Net I/σ(I): 14.4
Reflection shellResolution: 2.1→2.3 Å / Redundancy: 2 % / Rmerge(I) obs: 0.09 / Mean I/σ(I) obs: 2.5 / Rsym value: 0.25 / % possible all: 74
Reflection
*PLUS
Highest resolution: 2.1 Å / % possible obs: 79 % / Redundancy: 1.5 % / Num. measured all: 26856
Reflection shell
*PLUS
% possible obs: 74 %

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Processing

Software
NameVersionClassification
R-AXISIIdata collection
R-AXISIIdata reduction
X-PLORmodel building
PROLSQrefinement
X-PLORrefinement
R-AXISIIdata scaling
X-PLORphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1TMB

1tmb


Resolution: 2.1→7 Å / Cross valid method: THROUGHOUT / σ(F): 4
RfactorNum. reflection% reflection
Rwork0.157 --
obs-16839 75 %
Displacement parametersBiso mean: 20.7 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å / Luzzati d res low obs: 7 Å
Refinement stepCycle: LAST / Resolution: 2.1→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 37 134 2411
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.0150.02
X-RAY DIFFRACTIONp_angle_d0.0350.03
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d0.0550.05
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it1.11
X-RAY DIFFRACTIONp_mcangle_it1.81.5
X-RAY DIFFRACTIONp_scbond_it2.62
X-RAY DIFFRACTIONp_scangle_it3.82.5
X-RAY DIFFRACTIONp_plane_restr0.0270.03
X-RAY DIFFRACTIONp_chiral_restr0.150.2
X-RAY DIFFRACTIONp_singtor_nbd0.220.6
X-RAY DIFFRACTIONp_multtor_nbd0.310.6
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd0.280.6
X-RAY DIFFRACTIONp_planar_tor43
X-RAY DIFFRACTIONp_staggered_tor2015
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor3020
X-RAY DIFFRACTIONp_special_tor
Software
*PLUS
Name: PROLSQ / Classification: refinement
Refinement
*PLUS
Rfactor obs: 0.157
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 27.5 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONp_bond_d0.012
X-RAY DIFFRACTIONp_angle_d0.042

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