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- PDB-6z48: Crystal structure of Thrombin in complex with macrocycle X1vE -

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Basic information

Entry
Database: PDB / ID: 6z48
TitleCrystal structure of Thrombin in complex with macrocycle X1vE
Components
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE / serine protease / blood clotting factor / inhibition / macrocycle
Function / homology
Function and homology information


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 ...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 / 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
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. ...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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-X1V / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 Å
AuthorsAngelini, A. / Habeshian, S. / Heinis, C. / Cendron, L.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation157842 Switzerland
CitationJournal: Nat Commun / Year: 2022
Title: Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale.
Authors: Habeshian, S. / Merz, M.L. / Sangouard, G. / Mothukuri, G.K. / Schuttel, M. / Bognar, Z. / Diaz-Perlas, C. / Vesin, J. / Bortoli Chapalay, J. / Turcatti, G. / Cendron, L. / Angelini, A. / Heinis, C.
History
DepositionMay 23, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Thrombin light chain
H: Thrombin heavy chain
A: Thrombin light chain
B: Thrombin heavy chain
C: Thrombin light chain
D: Thrombin heavy chain
E: Thrombin light chain
F: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,10416
Polymers135,5078
Non-polymers2,5978
Water7,188399
1
L: Thrombin light chain
H: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5264
Polymers33,8772
Non-polymers6492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-22 kcal/mol
Surface area12770 Å2
MethodPISA
2
A: Thrombin light chain
B: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5264
Polymers33,8772
Non-polymers6492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-21 kcal/mol
Surface area12570 Å2
MethodPISA
3
C: Thrombin light chain
D: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5264
Polymers33,8772
Non-polymers6492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2230 Å2
ΔGint-22 kcal/mol
Surface area12940 Å2
MethodPISA
4
E: Thrombin light chain
F: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5264
Polymers33,8772
Non-polymers6492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-20 kcal/mol
Surface area12530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.251, 100.573, 108.897
Angle α, β, γ (deg.)90.000, 90.110, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide
Thrombin light chain


Mass: 4096.534 Da / Num. of mol.: 4 / Source method: isolated from a natural source
Details: >sp|P00734|328-363; missing residues are not visible in the electron density maps / disordered regions;
Source: (natural) Homo sapiens (human) / References: UniProt: P00734
#2: Protein
Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 4 / Source method: isolated from a natural source
Details: >sp|P00734|364-622; missing residues are not visible in the electron density maps / disordered regions
Source: (natural) Homo sapiens (human) / References: UniProt: P00734
#3: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#4: Chemical
ChemComp-X1V / 5-chloranyl-N-[[(4S,15R)-2,5,13,16-tetrakis(oxidanylidene)-15-propan-2-yl-9,10-dithia-3,6,14,17-tetrazabicyclo[17.3.1]tricosa-1(22),19(23),20-trien-4-yl]methyl]thiophene-2-carboxamide / macrocycle X1vE / 5-chloro-N-[[(4S,15R)-15-isopropyl-2,5,13,16-tetraoxo-9,10-dithia-3,6,14,17-tetrazabicyclo[17.3.1]tricosa-1(22),19(23),20-trien-4-yl]methyl]thiophene-2-carboxamide


Type: peptide-like / Mass: 626.211 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C26H32ClN5O5S3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 399 / Source method: isolated from a natural source / Formula: H2O
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: 2.38 Å3/Da / Density % sol: 48.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100 mM MOPS/sodium HEPES pH 7.5, 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.27→108.02 Å / Num. obs: 52645 / % possible obs: 93.86 % / Redundancy: 2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.041 / Net I/σ(I): 16.7
Reflection shellResolution: 2.27→2.35 Å / Rmerge(I) obs: 0.2527 / Num. unique obs: 4712 / CC1/2: 0.794

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
Aimlessdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GWE

6gwe


Resolution: 2.27→73.88 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2425 --RANDOM
Rwork0.1887 ---
obs-52631 93.86 %-
Displacement parametersBiso max: 135.43 Å2 / Biso mean: 28.0801 Å2 / Biso min: 5.48 Å2
Refinement stepCycle: LAST / Resolution: 2.27→73.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9098 0 164 399 9661

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