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- PDB-2y81: Structure and property based design of factor Xa inhibitors: pyrr... -

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Basic information

Entry
Database: PDB / ID: 2y81
TitleStructure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs
Components
  • ACTIVATED FACTOR XA HEAVY CHAIN
  • FACTOR X LIGHT CHAIN
KeywordsBLOOD CLOTTING / HYDROLASE / SERINE PROTEASE / BLOOD COAGULATION PROTEASE
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 / 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. ...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 / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-931 / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.7 Å
AuthorsYoung, R.J. / Adams, C. / Blows, M. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. ...Young, R.J. / Adams, C. / Blows, M. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Foster, G. / Harling, J.D. / Hortense, E. / Irving, W.R. / Irvine, S. / Jackson, S. / Kleanthous, S. / Pateman, A.J. / Patikis, A.N. / Roethka, T.J. / Senger, S. / Stelman, G.J. / Toomey, J.R. / West, R.I. / Whittaker, C. / Zhou, P. / Watson, N.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure and Property Based Design of Factor Xa Inhibitors: Pyrrolidin-2-Ones with Aminoindane and Phenylpyrrolidine P4 Motifs.
Authors: Young, R.J. / Adams, C. / Blows, M. / Brown, D. / Burns-Kurtis, C.L. / Chan, C. / Chaudry, L. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Foster, G. / Harling, J.D. / Hortense, E. / ...Authors: Young, R.J. / Adams, C. / Blows, M. / Brown, D. / Burns-Kurtis, C.L. / Chan, C. / Chaudry, L. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Foster, G. / Harling, J.D. / Hortense, E. / Irvine, S. / Irving, W.R. / Jackson, S. / Kleanthous, S. / Pateman, A.J. / Patikis, A.N. / Roethka, T.J. / Senger, S. / Stelman, G.J. / Toomey, J.R. / West, R.I. / Whittaker, C. / Zhou, P. / Watson, N.S.
History
DepositionFeb 2, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2011Provider: 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
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

Downloads & links

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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)44,3145
Polymers43,7612
Non-polymers5523
Water4,900272
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-32.1 kcal/mol
Surface area13360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.665, 72.033, 78.151
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein ACTIVATED FACTOR XA HEAVY CHAIN / COAGULATION FACTOR X / STUART FACTOR / STUART-PROWER FACTOR


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


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) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 4 types, 275 molecules

#3: Chemical ChemComp-931 / 6-CHLORO-N-((3S)-2-OXO-1-{4-[(2R)-2--PYRROLIDINYL] PHENYL}-3-PYRROLIDINYL)-2-NAPHTHALENESULFONAMIDE


Mass: 487.974 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23ClFN3O3S
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 272 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 1.81 Å3/Da / Density % sol: 49.3 % / 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% PEG 6K, 50 MM MES-NAOH (PH 5.5-6), 5 ...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% PEG 6K, 50 MM MES-NAOH (PH 5.5-6), 5 MM CACL2 AND 50 MM NACL.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.961
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 28, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.961 Å / Relative weight: 1
ReflectionResolution: 1.69→44.54 Å / Num. obs: 35816 / % possible obs: 97.6 % / Observed criterion σ(I): 0 / Redundancy: 5.5 % / Biso Wilson estimate: 20.615 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 14.4
Reflection shellResolution: 1.69→1.78 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 3.4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.7→20 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.935 / SU B: 2.119 / SU ML: 0.07 / Cross valid method: THROUGHOUT / ESU R: 0.106 / ESU R Free: 0.107 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22473 1753 5 %RANDOM
Rwork0.1861 ---
obs0.18801 33357 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.174 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2---1.07 Å20 Å2
3---1.18 Å2
Refinement stepCycle: LAST / Resolution: 1.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2222 0 35 272 2529
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222320
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3541.9643128
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0435283
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.22824.057106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.09415393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7141515
X-RAY DIFFRACTIONr_chiral_restr0.10.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211755
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_it1.2321414
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.32942259
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.0735906
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.8297869
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: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 129 -
Rwork0.257 2459 -
obs--100 %

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