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- PDB-6t7p: human plasmakallikrein protease domain in complex with active sit... -

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Basic information

Entry
Database: PDB / ID: 6t7p
Titlehuman plasmakallikrein protease domain in complex with active site directed inhibitor
ComponentsPlasma kallikrein
KeywordsHYDROLASE / S1 protease / serine protease / structure-based drug design / active site directed inhibitor
Function / homology
Function and homology information


plasma kallikrein / Factor XII activation / Defective SERPING1 causes hereditary angioedema / positive regulation of fibrinolysis / zymogen activation / plasminogen activation / Defective factor XII causes hereditary angioedema / Activation of Matrix Metalloproteinases / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation ...plasma kallikrein / Factor XII activation / Defective SERPING1 causes hereditary angioedema / positive regulation of fibrinolysis / zymogen activation / plasminogen activation / Defective factor XII causes hereditary angioedema / Activation of Matrix Metalloproteinases / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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. ...Apple domain. / Apple domain / APPLE domain / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
GLUTATHIONE / Chem-MU8 / PHOSPHATE ION / Plasma kallikrein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.416 Å
AuthorsRenatus, M.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.
Authors: Lorthiois, E. / Roache, J. / Barnes-Seeman, D. / Altmann, E. / Hassiepen, U. / Turner, G. / Duvadie, R. / Hornak, V. / Karki, R.G. / Schiering, N. / Weihofen, W.A. / Perruccio, F. / Calhoun, ...Authors: Lorthiois, E. / Roache, J. / Barnes-Seeman, D. / Altmann, E. / Hassiepen, U. / Turner, G. / Duvadie, R. / Hornak, V. / Karki, R.G. / Schiering, N. / Weihofen, W.A. / Perruccio, F. / Calhoun, A. / Fazal, T. / Dedic, D. / Durand, C. / Dussauge, S. / Fettis, K. / Tritsch, F. / Dentel, C. / Druet, A. / Liu, D. / Kirman, L. / Lachal, J. / Namoto, K. / Bevan, D. / Mo, R. / Monnet, G. / Muller, L. / Zessis, R. / Huang, X. / Lindsley, L. / Currie, T. / Chiu, Y.H. / Fridrich, C. / Delgado, P. / Wang, S. / Hollis-Symynkywicz, M. / Berghausen, J. / Williams, E. / Liu, H. / Liang, G. / Kim, H. / Hoffmann, P. / Hein, A. / Ramage, P. / D'Arcy, A. / Harlfinger, S. / Renatus, M. / Ruedisser, S. / Feldman, D. / Elliott, J. / Sedrani, R. / Maibaum, J. / Adams, C.M.
History
DepositionOct 22, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Plasma kallikrein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,92515
Polymers27,1871
Non-polymers1,73814
Water4,810267
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2980 Å2
ΔGint12 kcal/mol
Surface area11640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.100, 59.150, 86.720
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Plasma kallikrein / Fletcher factor / Kininogenin / Plasma prekallikrein / PKK


Mass: 27186.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KLKB1, KLK3 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): DE3 Rosetta / References: UniProt: P03952, plasma kallikrein

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Non-polymers , 6 types, 281 molecules

#2: Chemical ChemComp-GSH / GLUTATHIONE


Mass: 307.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N3O6S
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-MU8 / (2~{S},4~{R})-1-[[(3~{S})-3-azanyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl]-~{N}-(3-chlorophenyl)-4-phenyl-pyrrolidine-2-carboxamide


Mass: 461.940 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 267 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.69 Å3/Da / Density % sol: 54.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20% PEG10000, 200 mM Sodium phosphate (monobasic), corresponds to Nextal condition #87 from PEG series

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: May 28, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.416→37.126 Å / Num. obs: 56111 / % possible obs: 99.1 % / Redundancy: 4.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.049 / Rpim(I) all: 0.027 / Rrim(I) all: 0.057 / Net I/σ(I): 15.4
Reflection shellResolution: 1.416→1.421 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.549 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1920 / CC1/2: 0.847 / Rpim(I) all: 0.417 / Rrim(I) all: 0.639 / % possible all: 93.3

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
MOLREP8.2.01phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2any

2any


Resolution: 1.416→37.126 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 17.47
RfactorNum. reflection% reflection
Rfree0.1878 2807 5 %
Rwork0.1524 --
obs0.1542 56101 99.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 130.47 Å2 / Biso mean: 24.8591 Å2 / Biso min: 4.74 Å2
Refinement stepCycle: final / Resolution: 1.416→37.126 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1877 0 116 268 2261
Biso mean--38.86 35.94 -
Num. residues----237
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.416-1.440.25481340.2166250294
1.4402-1.46640.22981390.2028264299
1.4664-1.49460.28061390.19252643100
1.4946-1.52510.26371390.19882654100
1.5251-1.55830.23621390.19112640100
1.5583-1.59450.21871400.16792677100
1.5945-1.63440.2231430.15812668100
1.6344-1.67860.20921400.14422638100
1.6786-1.7280.18771400.14062677100
1.728-1.78370.16641390.14082654100
1.7837-1.84750.1891400.1407265599
1.8475-1.92150.17571400.1399263999
1.9215-2.00890.17181390.1363264499
2.0089-2.11480.18011410.1353267999
2.1148-2.24730.18321390.1419264299
2.2473-2.42080.16261400.145269099
2.4208-2.66430.19891410.1566269799
2.6643-3.04970.19071430.1645271799
3.0497-3.84170.18631440.1447273799

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