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- PDB-2wyg: Structure and property based design of factor Xa inhibitors: pyrr... -

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Basic information

Entry
Database: PDB / ID: 2wyg
TitleStructure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs
Components
  • ACTIVATED FACTOR XA HEAVY CHAIN
  • FACTOR X LIGHT CHAIN
KeywordsBLOOD CLOTTING / SERINE PROTEASE / EGF-LIKE DOMAIN / BLOOD COAGULATION / HYDROLASE / HYDROXYLATION / ZYMOGEN
Function / homology
Function and homology information


coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / 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 ...coagulation factor Xa / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / Extrinsic Pathway of Fibrin Clot Formation / positive regulation of TOR signaling / 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 / Intrinsic Pathway of Fibrin Clot Formation / phospholipid binding / Golgi lumen / blood coagulation / positive regulation of cell migration / endoplasmic reticulum lumen / external side of plasma membrane / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Laminin / Laminin / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / 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 / 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 family, serine 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
Chem-461 / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsKleanthous, S. / Borthwick, A.D. / Brown, D. / Burns-Kurtis, C.L. / Campbell, M. / Chaudry, L. / Chan, C. / Clarte, M. / Convery, M.A. / Harling, J.D. ...Kleanthous, S. / Borthwick, A.D. / Brown, D. / Burns-Kurtis, C.L. / Campbell, M. / Chaudry, L. / Chan, C. / Clarte, M. / Convery, M.A. / Harling, J.D. / Hortense, E. / Irving, W.R. / Irvine, S. / Pateman, A.J. / Patikis, A. / Pinto, I.L. / Pollard, D.R. / Roethka, T.J. / Senger, S. / Shah, G.P. / Stelman, G.J. / Toomey, J.R. / Watson, N.S. / Whittaker, C. / Zhou, P. / Young, R.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure and Property Based Design of Factor Xa Inhibitors: Pyrrolidin-2-Ones with Monoaryl P4 Motifs
Authors: Kleanthous, S. / Borthwick, A.D. / Brown, D. / Burns-Kurtis, C.L. / Campbell, M. / Chaudry, L. / Chan, C. / Clarte, M. / Convery, M.A. / Harling, J.D. / Hortense, E. / Irving, W.R. / Irvine, ...Authors: Kleanthous, S. / Borthwick, A.D. / Brown, D. / Burns-Kurtis, C.L. / Campbell, M. / Chaudry, L. / Chan, C. / Clarte, M. / Convery, M.A. / Harling, J.D. / Hortense, E. / Irving, W.R. / Irvine, S. / Pateman, A.J. / Patikis, A. / Pinto, I.L. / Pollard, D.R. / Roethka, T.J. / Senger, S. / Shah, G.P. / Stelman, G.J. / Toomey, J.R. / Watson, N.S. / Whittaker, C. / Zhou, P. / Young, R.J.
History
DepositionNov 16, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 1, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 16, 2019Group: Data collection / Experimental preparation / Other / Category: exptl_crystal_grow / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.status_code_sf
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ACTIVATED FACTOR XA HEAVY CHAIN
B: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2333
Polymers43,7612
Non-polymers4721
Water3,783210
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-9.9 kcal/mol
Surface area13110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.673, 72.814, 78.509
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein ACTIVATED FACTOR XA HEAVY CHAIN


Mass: 28550.596 Da / Num. of mol.: 1 / Fragment: ACTIVATED DESGLA, RESIDUES 235-488 / Source method: isolated from a natural source
Details: PURCHASED FROM ENZYME RESEARCH LABS, ISOLATED FROM HUMAN BLOOD
Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00742, coagulation factor Xa
#2: Protein FACTOR X LIGHT CHAIN


Mass: 15210.793 Da / Num. of mol.: 1 / Fragment: ACTIVATED DESGLA, RESIDUES 46-179 / Source method: isolated from a natural source
Details: PURCHASED FROM ENZYME RESEARCH LABS, ISOLATED FROM HUMAN BLOOD
Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00742, coagulation factor Xa
#3: Chemical ChemComp-461 / (E)-2-(5-CHLOROTHIOPHEN-2-YL)-N-[(3S)-1-{4-[(1R)-1-(DIMETHYLAMINO)ETHYL]-2-FLUOROPHENYL}-2-OXOPYRROLIDIN-3-YL]ETHENESULFONAMIDE


Mass: 471.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23ClFN3O3S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsSOME RESIDUES IN CHAIN ARE NOT SEEN IN THE ELECTRON DENSITY. SEQUENCE DATABASE RESIDUES 1-45 (THE ...SOME RESIDUES IN CHAIN ARE NOT SEEN IN THE ELECTRON DENSITY. SEQUENCE DATABASE RESIDUES 1-45 (THE GLA DOMAIN) WERE BIOCHEMICALLY REMOVED IN CHAIN B

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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: 1.85 Å3/Da / Density % sol: 33.54 % / Description: NONE
Crystal growMethod: vapor diffusion / pH: 5.75
Details: CRYSTALLISATION WAS CARRIED OUT USING VAPOUR DIFFUSION IN 2UL DROPS CONTAINING A 1:1 MIXTURE OF PROTEIN AND WELL SOLUTION. WELL SOLUTION CONTAINED 16-20% PEG6K, 50MM MES-NAOH (PH5.5-6), 5MM ...Details: CRYSTALLISATION WAS CARRIED OUT USING VAPOUR DIFFUSION IN 2UL DROPS CONTAINING A 1:1 MIXTURE OF PROTEIN AND WELL SOLUTION. WELL SOLUTION CONTAINED 16-20% PEG6K, 50MM MES-NAOH (PH5.5-6), 5MM CACL2 AND 50MM NACL., pH 5.75

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9393
DetectorType: ADSC CCD / Detector: CCD / Date: Nov 30, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9393 Å / Relative weight: 1
ReflectionResolution: 1.88→30 Å / Num. obs: 26765 / % possible obs: 99.2 % / Observed criterion σ(I): 0 / Redundancy: 7.26 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 21.6
Reflection shellResolution: 1.88→1.97 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 4 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.4.0073refinement
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1EZQ

1ezq


Resolution: 1.88→29.49 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.922 / SU B: 2.898 / SU ML: 0.087 / Cross valid method: THROUGHOUT / ESU R: 0.148 / ESU R Free: 0.139 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23446 1346 5 %RANDOM
Rwork0.19566 ---
obs0.19759 25362 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.686 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å20 Å2
2---1.44 Å20 Å2
3---1.33 Å2
Refinement stepCycle: LAST / Resolution: 1.88→29.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2182 0 30 210 2422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222285
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4621.963095
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.055281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.92623.883103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.34515386
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.8741515
X-RAY DIFFRACTIONr_chiral_restr0.0960.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211735
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.41521394
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.71142245
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.5795891
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.6177850
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.88→1.929 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 79 -
Rwork0.242 1711 -
obs--100 %

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