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- PDB-3tu7: Human alpha-thrombin complexed with N-(methylsulfonyl)-D-phenylal... -

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Basic information

Entry
Database: PDB / ID: 3tu7
TitleHuman alpha-thrombin complexed with N-(methylsulfonyl)-D-phenylalanyl-N-((1-carbamimidoyl-4-piperidinyl)methyl)-l-prolinamide (BMS-189664)
Components
  • (Prothrombin) x 2
  • Hirudin variant-2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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
N-(METHYLSULFONYL)-D-PHENYLALANYL-N-[(1-CARBAMIMIDOYLPIPERIDIN-4-YL)METHYL]-L-PROLINAMIDE / Chem-0BM / Prothrombin / Hirudin variant-1 / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsMalley, M. / Sack, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2002
Title: Molecular design and structure-activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.
Authors: Das, J. / Kimball, S.D. / Hall, S.E. / Han, W.C. / Iwanowicz, E. / Lin, J. / Moquin, R.V. / Reid, J.A. / Sack, J.S. / Malley, M.F. / Chang, C.Y. / Chong, S. / Wang-Iverson, D.B. / Roberts, D. ...Authors: Das, J. / Kimball, S.D. / Hall, S.E. / Han, W.C. / Iwanowicz, E. / Lin, J. / Moquin, R.V. / Reid, J.A. / Sack, J.S. / Malley, M.F. / Chang, C.Y. / Chong, S. / Wang-Iverson, D.B. / Roberts, D.G. / Seiler, S.M. / Schumacher, W.A. / Ogletree, M.L.
History
DepositionSep 16, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Other

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Prothrombin
H: Prothrombin
I: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9044
Polymers35,4253
Non-polymers4791
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3710 Å2
ΔGint-19 kcal/mol
Surface area12690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.219, 48.952, 43.631
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein/peptide Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: Thrombin light chain / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: PLASMA / References: UniProt: P00734, thrombin
#2: Protein Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: Thrombin heavy chain / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: PLASMA / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-2


Mass: 1548.496 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Hirudo medicinalis (medicinal leech) / Tissue: PLASMA / References: UniProt: P09945, UniProt: P01050*PLUS
#4: Chemical ChemComp-0BM / N-(methylsulfonyl)-D-phenylalanyl-N-[(1-carbamimidoylpiperidin-4-yl)methyl]-L-prolinamide


Type: Peptide-like / Class: Thrombin inhibitor / Mass: 478.608 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H34N6O4S
References: N-(METHYLSULFONYL)-D-PHENYLALANYL-N-[(1-CARBAMIMIDOYLPIPERIDIN-4-YL)METHYL]-L-PROLINAMIDE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.48 Å3/Da / Density % sol: 50.31 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Oct 19, 1994 / Details: GOEBEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.49→50 Å / Num. obs: 10565 / % possible obs: 81.6 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 32.88 Å2 / Rmerge(I) obs: 0.086 / Net I/σ(I): 10.9
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.082 / Mean I/σ(I) obs: 9.5 / % possible all: 63.9

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.49→46.91 Å / Cor.coef. Fo:Fc: 0.9442 / Cor.coef. Fo:Fc free: 0.9101 / SU R Cruickshank DPI: 0.696 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2298 510 4.83 %RANDOM
Rwork0.1593 ---
obs0.1625 10550 81.24 %-
Displacement parametersBiso mean: 23.05 Å2
Baniso -1Baniso -2Baniso -3
1-5.7387 Å20 Å20 Å2
2---3.1145 Å20 Å2
3----2.6242 Å2
Refine analyzeLuzzati coordinate error obs: 0.232 Å
Refinement stepCycle: LAST / Resolution: 2.49→46.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2337 0 33 44 2414
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012432HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.263291HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d853SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes355HARMONIC5
X-RAY DIFFRACTIONt_it2432HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion21.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
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_contact2629SEMIHARMONIC4
LS refinement shellResolution: 2.49→2.78 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2941 134 5.53 %
Rwork0.1638 2287 -
all0.1707 2421 -
obs--81.24 %

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