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- PDB-1o5d: Dissecting and Designing Inhibitor Selectivity Determinants at th... -

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Entry
Database: PDB / ID: 1o5d
TitleDissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
Components
  • (Coagulation factor VII) x 2
  • Tissue factor
KeywordsBLOOD CLOTTING / hydrolase / Ala190 uPA / S1 site / selectivity / conserved water displacement hydrogen bond deficit / trypsin / thrombin / hepsin / factor VIIa
Function / homology
Function and homology information


activation of plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway ...activation of plasma proteins involved in acute inflammatory response / activation of blood coagulation via clotting cascade / coagulation factor VIIa / response to Thyroid stimulating hormone / response to 2,3,7,8-tetrachlorodibenzodioxine / response to astaxanthin / response to thyrotropin-releasing hormone / response to genistein / serine-type peptidase complex / positive regulation of platelet-derived growth factor receptor signaling pathway / response to vitamin K / response to carbon dioxide / response to thyroxine / positive regulation of leukocyte chemotaxis / NGF-stimulated transcription / response to cholesterol / response to growth hormone / cytokine receptor activity / positive regulation of positive chemotaxis / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / positive regulation of blood coagulation / animal organ regeneration / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Removal of aminoterminal propeptides from gamma-carboxylated proteins / positive regulation of endothelial cell proliferation / serine-type peptidase activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / positive regulation of interleukin-8 production / phospholipid binding / protein processing / Golgi lumen / cytokine-mediated signaling pathway / circadian rhythm / response to estrogen / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of angiogenesis / blood coagulation / response to estradiol / collagen-containing extracellular matrix / protease binding / vesicle / response to hypoxia / positive regulation of cell migration / endoplasmic reticulum lumen / external side of plasma membrane / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of gene expression / cell surface / extracellular space / extracellular region / membrane / plasma membrane
Similarity search - Function
Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin ...Tissue factor / Tissue factor, conserved site / Tissue factor signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / Tissue factor / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / Laminin / Laminin / EGF-type aspartate/asparagine hydroxylation site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like 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. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Fibronectin type III / Fibronectin type III superfamily / Ribbon / 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 / Immunoglobulins / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Immunoglobulin-like fold / Immunoglobulin-like / Beta Barrel / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-CR9 / Coagulation factor VII / Tissue factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.05 Å
AuthorsKatz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. ...Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
CitationJournal: J.Mol.Biol. / Year: 2004
Title: Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).
Authors: Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
History
DepositionSep 9, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 4, 2017Group: Refinement description / Category: software
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Coagulation factor VII
H: Coagulation factor VII
T: Tissue factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,2724
Polymers69,8903
Non-polymers3821
Water10,593588
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5560 Å2
ΔGint-10 kcal/mol
Surface area22360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.54, 69.03, 79.12
Angle α, β, γ (deg.)90.0, 89.99, 90.0
Int Tables number4
Cell settingmonoclinic
Space group name H-MP1211

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Components

#1: Protein Coagulation factor VII / / E.C.3.4.21.21 / Serum prothrombin conversion accelerator / Eptacog alfa


Mass: 17046.975 Da / Num. of mol.: 1 / Fragment: light chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Plasmid: pCI-neo(Promega) / Cell line (production host): 293 / Organ (production host): embryonic kidney / Production host: Homo sapiens (human) / References: UniProt: P08709, coagulation factor VIIa
#2: Protein Coagulation factor VII / / E.C.3.4.21.21 / Serum prothrombin conversion accelerator / Eptacog alfa


Mass: 28103.256 Da / Num. of mol.: 1 / Fragment: heavy chain (catalytic domain)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F7 / Plasmid: pCI-neo(Promega) / Cell line (production host): 293 / Organ (production host): embryonic kidney / Production host: Homo sapiens (human) / References: UniProt: P08709, coagulation factor VIIa
#3: Protein Tissue factor / / TF / Coagulation factor III / Thromboplastin / CD142 antigen


Mass: 24739.434 Da / Num. of mol.: 1 / Mutation: residues 2-219
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: ESCHERICHIA COLI / Gene: F3 / Plasmid: pET-21a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-DES3 / References: UniProt: P13726
#4: Chemical ChemComp-CR9 / 2-{5-[AMINO(IMINIO)METHYL]-6-FLUORO-1H-BENZIMIDAZOL-2-YL}-6-[(2-METHYLCYCLOHEXYL)OXY]BENZENOLATE / CRA_11092


Mass: 382.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23FN4O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 588 / 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: 3.07 Å3/Da / Density % sol: 59.92 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7.2
Details: 0.1 M citrate, 16-18% PEG 5K MME, pH 7.2, vapor diffusion at 290 K

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 7, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→20 Å / Num. all: 52825 / Num. obs: 50184 / % possible obs: 95 % / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 7.7
Reflection shellResolution: 2.05→2.14 Å / % possible obs: 49.5 % / Rmerge(I) obs: 0.288 / Num. unique all: 6460

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Processing

Software
NameVersionClassification
ALS Berkeley beamline 5.0.2data collection
DENZO1.97.2data reduction
X-PLOR3.851refinement
SCALEPACKdata scaling
Quantamodel building
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.05→7 Å / Cross valid method: THROUGHOUT / σ(F): 2.4 / Stereochemistry target values: X-PLOR force field
Details: The Gla domain of the light chain (residue Ala L1 through Asp L46) is not visible (disordered). Some of the soluble tissue factor is not visible (disordered): Gly_T2 through Asn_T5;Gln T110 ...Details: The Gla domain of the light chain (residue Ala L1 through Asp L46) is not visible (disordered). Some of the soluble tissue factor is not visible (disordered): Gly_T2 through Asn_T5;Gln T110 through Glu T128; Trp T158 through Phe T187; Pro T206 through Met T210. Many of the waters may correspond to sporadic density in the regions of diordered protein. Residues simultaneously refined in two or more conformations are: Leu_L121, Lys_L137, Val_H138, Lys_H188, Ser_H190, Ser_T42 Discretely disordered waters are: HOH_94; A_HOH_578 is close to B_HOH578 which is close to A_HOH_581 which is close to B_HOH_581. HOH_858; HIS_H57 is doubly protonated. HIS_H91 is monoprotonated on the epsilon nitrogen No energy terms are included Og_Ser_H195, and O6' and HN3 of the inhibitor. These atoms form a short hydrogen-bonding network.
RfactorNum. reflection% reflection
Rfree0.262 4073 10 %
Rwork0.226 --
obs0.228 40130 77.32 %
all-51903 -
Refinement stepCycle: LAST / Resolution: 2.05→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7766 0 51 1776 9593
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.019
X-RAY DIFFRACTIONx_angle_deg3.9

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