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- PDB-6bx8: Human Mesotrypsin (PRSS3) Complexed with Tissue Factor Pathway In... -

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Basic information

Entry
Database: PDB / ID: 6bx8
TitleHuman Mesotrypsin (PRSS3) Complexed with Tissue Factor Pathway Inhibitor Variant (TFPI1-KD1-K15R-I17C-I34C)
Components
  • Tissue factor pathway inhibitor
  • Trypsin-3
KeywordsHYDROLASE / Hydrolase Inhibitor
Function / homology
Function and homology information


Uptake of dietary cobalamins into enterocytes / negative regulation of blood coagulation / antimicrobial humoral response / Alpha-defensins / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Antimicrobial peptides / endopeptidase inhibitor activity / cellular response to steroid hormone stimulus / endothelial cell migration ...Uptake of dietary cobalamins into enterocytes / negative regulation of blood coagulation / antimicrobial humoral response / Alpha-defensins / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Antimicrobial peptides / endopeptidase inhibitor activity / cellular response to steroid hormone stimulus / endothelial cell migration / trypsin / side of membrane / digestion / serine-type peptidase activity / caveola / serine-type endopeptidase inhibitor activity / blood coagulation / tertiary granule lumen / serine-type endopeptidase activity / calcium ion binding / Neutrophil degranulation / cell surface / endoplasmic reticulum / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Tissue factor pathway inhibitor-like / Pancreatic trypsin inhibitor Kunitz domain / Factor Xa Inhibitor / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily ...Tissue factor pathway inhibitor-like / Pancreatic trypsin inhibitor Kunitz domain / Factor Xa Inhibitor / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / Few Secondary Structures / Irregular / Serine proteases, trypsin family, histidine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine 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
Tissue factor pathway inhibitor / Trypsin-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.98 Å
AuthorsCoban, M. / Sankaran, B. / Cohen, I. / Hockla, A. / Papo, N. / Radisky, E.S.
Funding support United States, Israel, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)R01CA154387 United States
United States - Israel Binational Science Foundation (BSF)BSF2015134 Israel
Citation
Journal: J. Biol. Chem. / Year: 2019
Title: Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.
Authors: Cohen, I. / Coban, M. / Shahar, A. / Sankaran, B. / Hockla, A. / Lacham, S. / Caulfield, T.R. / Radisky, E.S. / Papo, N.
#1: Journal: Acta Crystallogr. D Biol. Crystallogr. / Year: 2008
Title: Model preparation in MOLREP and examples of model improvement using X-ray data.
Authors: Lebedev, A.A. / Vagin, A.A. / Murshudov, G.N.
#2: Journal: Acta Crystallogr. D Biol. Crystallogr. / Year: 1997
Title: Refinement of macromolecular structures by the maximum-likelihood method.
Authors: Murshudov, G.N. / Vagin, A.A. / Dodson, E.J.
#3: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2004
Title: Coot: model-building tools for molecular graphics.
Authors: Paul Emsley / Kevin Cowtan /
Abstract: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality ...CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
#4: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2010
Title: PHENIX: a comprehensive Python-based system for macromolecular structure solution.
Authors: Paul D Adams / Pavel V Afonine / Gábor Bunkóczi / Vincent B Chen / Ian W Davis / Nathaniel Echols / Jeffrey J Headd / Li-Wei Hung / Gary J Kapral / Ralf W Grosse-Kunstleve / Airlie J McCoy ...Authors: Paul D Adams / Pavel V Afonine / Gábor Bunkóczi / Vincent B Chen / Ian W Davis / Nathaniel Echols / Jeffrey J Headd / Li-Wei Hung / Gary J Kapral / Ralf W Grosse-Kunstleve / Airlie J McCoy / Nigel W Moriarty / Robert Oeffner / Randy J Read / David C Richardson / Jane S Richardson / Thomas C Terwilliger / Peter H Zwart /
Abstract: Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many ...Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
#5: Journal: Acta Crystallogr. D Biol. Crystallogr. / Year: 2010
Title: MolProbity: all-atom structure validation for macromolecular crystallography.
Authors: Chen, V.B. / Arendall, W.B. / Headd, J.J. / Keedy, D.A. / Immormino, R.M. / Kapral, G.J. / Murray, L.W. / Richardson, J.S. / Richardson, D.C.
History
DepositionDec 18, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 13, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 10, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Trypsin-3
B: Tissue factor pathway inhibitor
C: Trypsin-3
D: Tissue factor pathway inhibitor
E: Trypsin-3
F: Tissue factor pathway inhibitor
G: Trypsin-3
H: Tissue factor pathway inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,14112
Polymers135,7578
Non-polymers3844
Water14,790821
1
A: Trypsin-3
B: Tissue factor pathway inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0353
Polymers33,9392
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint-17 kcal/mol
Surface area11340 Å2
MethodPISA
2
C: Trypsin-3
D: Tissue factor pathway inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0353
Polymers33,9392
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1560 Å2
ΔGint-18 kcal/mol
Surface area11440 Å2
MethodPISA
3
E: Trypsin-3
F: Tissue factor pathway inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0353
Polymers33,9392
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1580 Å2
ΔGint-17 kcal/mol
Surface area11320 Å2
MethodPISA
4
G: Trypsin-3
H: Tissue factor pathway inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0353
Polymers33,9392
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-18 kcal/mol
Surface area11570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.137, 87.199, 90.840
Angle α, β, γ (deg.)94.810, 93.030, 92.460
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Trypsin-3 / / Brain trypsinogen / Mesotrypsinogen / Serine protease 3 / Serine protease 4 / Trypsin III / Trypsin IV


Mass: 24257.457 Da / Num. of mol.: 4 / Mutation: S257A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRSS3, PRSS4, TRY3, TRY4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P35030, trypsin
#2: Protein
Tissue factor pathway inhibitor / / TFPI / Extrinsic pathway inhibitor / EPI / Lipoprotein-associated coagulation inhibitor / LACI


Mass: 9681.825 Da / Num. of mol.: 4 / Mutation: K64R, M66C, I83C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TFPI, LACI, TFPI1 / Production host: Komagataella pastoris (fungus) / References: UniProt: P10646
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 821 / 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: 2.04 Å3/Da / Density % sol: 39.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.2M Lithium Sulfate, 0.1M BIS-Tris-HCl pH 4.6, 25% v/v PEG 3350 (Anatrace Top96-27)

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Data collection

DiffractionMean temperature: 80 K / Ambient temp details: LN2
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.98→60.0901 Å / Num. obs: 70450 / % possible obs: 97.4 % / Redundancy: 1.7 % / Biso Wilson estimate: 19.36 Å2 / CC1/2: 0.97 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.067 / Rrim(I) all: 0.095 / Net I/σ(I): 6.5
Reflection shellResolution: 1.98→2.05 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.249 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 7014 / CC1/2: 0.887 / Rpim(I) all: 0.249 / Rrim(I) all: 0.352 / % possible all: 93.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.58
Highest resolutionLowest resolution
Rotation60.06 Å1.91 Å

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimless0.5.32data scaling
MOLREP11.5.05phasing
PDB_EXTRACT3.24data extraction
DIALS1.2.2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P95, 4BQD

3p95

4bqd


Resolution: 1.98→60.062 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 22.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 3375 4.86 %RANDOM
Rwork0.1922 66081 --
obs0.1936 69456 93.04 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 92.38 Å2 / Biso mean: 30.0686 Å2 / Biso min: 9.88 Å2
Refinement stepCycle: final / Resolution: 1.98→60.062 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8217 0 20 821 9058
Biso mean--50.53 41.1 -
Num. residues----1113
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.98-2.00830.28551390.26962720285993
2.0083-2.03830.26211430.24982813295694
2.0383-2.07010.33351250.37392627275287
2.0701-2.10410.28571160.29052599271589
2.1041-2.14030.23181420.20592748289094
2.1403-2.17930.23551390.20262838297793
2.1793-2.22120.24881170.26232621273888
2.2212-2.26650.46741180.45092280239878
2.2665-2.31580.22941540.21322741289592
2.3158-2.36970.22971500.18182775292595
2.3697-2.42890.20181550.16922739289494
2.4289-2.49460.20111240.16622764288892
2.4946-2.5680.19991450.16682748289393
2.568-2.65090.24021510.17082812296395
2.6509-2.74570.19841670.16842794296194
2.7457-2.85560.20671530.16212796294996
2.8556-2.98560.20911660.16642857302396
2.9856-3.14290.2011610.15562767292895
3.1429-3.33980.18361470.15712777292494
3.3398-3.59770.21721130.16732844295795
3.5977-3.95970.2053980.16642880297895
3.9597-4.53250.1791790.14152837301698
4.5325-5.70980.18611390.16842860299996
5.7098-60.09010.23711340.2232844297896

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