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- PDB-1doj: Crystal structure of human alpha-thrombin*RWJ-51438 complex at 1.7 A -

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Entry
Database: PDB / ID: 1doj
TitleCrystal structure of human alpha-thrombin*RWJ-51438 complex at 1.7 A
Components
  • ALPHA-THROMBIN
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / thrombin / serine protease / enzyme inhibition / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


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 ...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) / 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
RWJ-51438 / Chem-1Z0 / Prothrombin / Hirudin variant-2 / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.7 Å
AuthorsRecacha, R. / Costanzo, M.J. / Maryanoff, B.E. / Carson, M. / DeLucas, L. / Chattopadhyay, D.
Citation
Journal: Acta Crystallogr.,Sect.D / Year: 2000
Title: Structure of human alpha-thrombin complexed with RWJ-51438 at 1.7 A: unusual perturbation of the 60A-60I insertion loop.
Authors: Recacha, R. / Costanzo, M.J. / Maryanoff, B.E. / Carson, M. / DeLucas, L. / Chattopadhyay, D.
#1: Journal: Biochemistry / Year: 1992
Title: Structure of the Hirulog 3-Thrombin Complex and Nature of the S' Subsites of Substrates and Inhibitors
Authors: Qiu, X. / Padmanabhan, K.P. / Carperos, V.E. / Tulinsky, A. / Kline, T. / Maraganore, J.M. / Fenton II, J.W.
#2: Journal: Biophys.J. / Year: 1996
Title: Crystal Structure of Thrombin with Thiazole-Containing Inhibitors: Probes of the S1' Binding Site
Authors: Matthews, J.H. / Krishnan, R. / Costanzo, M.J. / Maryanoff, B.E. / Tulinsky, A.
#3: Journal: Protein Sci. / Year: 1992
Title: The Refined 1.9-A X-ray Crystal Structure of D-Pro-Phe-Arg Chloromethylketone-Inhibited Human Alpha-Thrombin: Structure Analysis, Overall Structure, Electrostatic Properties, Detailed Active- ...Title: The Refined 1.9-A X-ray Crystal Structure of D-Pro-Phe-Arg Chloromethylketone-Inhibited Human Alpha-Thrombin: Structure Analysis, Overall Structure, Electrostatic Properties, Detailed Active-Site Geometry, and Structure-Function Relationships
Authors: Bode, W. / Turk, D. / Karshikov, A.
History
DepositionDec 21, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 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 1.4Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / 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_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_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
Revision 1.5Mar 13, 2024Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_src_syn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.details
Revision 1.6Oct 30, 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
A: ALPHA-THROMBIN
B: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2116
Polymers35,3502
Non-polymers8614
Water6,287349
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.982, 117.521, 47.989
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein / Protein/peptide / Sugars , 3 types, 3 molecules AB

#1: Protein ALPHA-THROMBIN


Mass: 33858.730 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cellular location: PLASMA / References: UniProt: P00734, thrombin
#2: Protein/peptide HIRUGEN


Mass: 1491.528 Da / Num. of mol.: 1 / Fragment: FRAGMENT OF HIRUDIN / Source method: obtained synthetically / Details: Hirugen, comes from hirudin / References: UniProt: P09945, UniProt: P28504*PLUS
#4: 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 , 3 types, 352 molecules

#3: Chemical ChemComp-1Z0 / N-methyl-D-phenylalanyl-N-{(1S)-4-carbamimidamido-1-[(6-carboxy-1,3-benzothiazol-2-yl)carbonyl]butyl}-L-prolinamide / RWJ-51438


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 593.697 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H35N7O5S
Details: RWJ-51438 IS JOINED COVALENTLY TO SER195 OF HUMAN ALPHA-THROMBIN RWJ-51438 was chemically synthesized
References: RWJ-51438
#5: Chemical ChemComp-NA / SODIUM ION


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


Mass: 18.015 Da / Num. of mol.: 349 / 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: 2.47 Å3/Da / Density % sol: 50.21 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.75 sodium acetate, 0.01% (w/v), 20% polyethylene glycol 4000 (w/v), pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 295.0K
Crystal grow
*PLUS
pH: 7.3
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
150 mMphosphate1drop
26 mg/mlprotein1drop
30.1 Msodium cacodylate1reservoir
40.75 Msodium acetate1reservoir
50.01 %(w/v)sodium azide1reservoir
620 %(w/v)PEG40001reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Mar 4, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.66→99 Å / Num. all: 126549 / Num. obs: 126549 / % possible obs: 87.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5 % / Biso Wilson estimate: 16.2 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 16.3
Reflection shellHighest resolution: 1.66 Å / Redundancy: 3 % / Rmerge(I) obs: 0.2 / % possible all: 87.1
Reflection
*PLUS
Num. obs: 42979 / Num. measured all: 289770
Reflection shell
*PLUS
Lowest resolution: 1.72 Å / % possible obs: 43 % / Rmerge(I) obs: 0.2

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
X-PLOR3.851refinement
RefinementResolution: 1.7→8 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1520225.35 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 3 / σ(I): 0 / Details: The Bijvoet differences were used in phasing
RfactorNum. reflection% reflectionSelection details
Rfree0.217 3322 10 %RANDOM
Rwork0.174 ---
obs0.174 33357 84.2 %-
all-39616 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 93.48 Å2 / ksol: 0.49 e/Å3
Displacement parametersBiso mean: 19.5 Å2
Baniso -1Baniso -2Baniso -3
1-1.02 Å20 Å20 Å2
2---1.45 Å20 Å2
3---0.43 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.21 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.13 Å
Refinement stepCycle: LAST / Resolution: 1.7→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2452 0 58 349 2859
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d26.3
X-RAY DIFFRACTIONc_improper_angle_d0.61
X-RAY DIFFRACTIONc_mcbond_it1.41.5
X-RAY DIFFRACTIONc_mcangle_it2.062
X-RAY DIFFRACTIONc_scbond_it2.422
X-RAY DIFFRACTIONc_scangle_it3.482.5
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.298 3670 10 %
Rwork0.276 3311 -
obs--56.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMTOPHCSDX.PRO
X-RAY DIFFRACTION2INH3.PARAMTOPH19.SOL
X-RAY DIFFRACTION3ION.PARAMINH2.TOP
X-RAY DIFFRACTION4NAG.PARAMNAG.TOP
X-RAY DIFFRACTION5SULF.TOP
Software
*PLUS
Name: X-PLOR / Version: 3.851 / Classification: refinement
Refinement
*PLUS
Num. reflection obs: 35906 / σ(F): 3 / % reflection Rfree: 4.5 % / Rfactor obs: 0.196 / Rfactor Rfree: 0.232
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 19.5 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.01
X-RAY DIFFRACTIONx_angle_deg1.4
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg26.3
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.61
X-RAY DIFFRACTIONx_mcbond_it1.5
X-RAY DIFFRACTIONx_scbond_it2
X-RAY DIFFRACTIONx_mcangle_it2
X-RAY DIFFRACTIONx_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.298 / % reflection Rfree: 10 % / Rfactor Rwork: 0.276

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