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- PDB-2y7x: The discovery of potent and long-acting oral factor Xa inhibitors... -

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Basic information

Entry
Database: PDB / ID: 2y7x
TitleThe discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs
Components
  • ACTIVATED FACTOR XA HEAVY CHAIN
  • FACTOR X LIGHT CHAIN
KeywordsBLOOD CLOTTING / HYDROLASE / SERINE 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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / 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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / 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 1. / EGF-like domain signature 2. / EGF-like domain / Ribbon / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / 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-MZA / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.9 Å
AuthorsWatson, N.S. / Adams, C. / Belton, D. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. ...Watson, N.S. / Adams, C. / Belton, D. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Harling, J.D. / Irving, W.R. / Irvine, S. / Kleanthous, S. / McLay, I.M. / Pateman, A.J. / Patikis, A.N. / Roethka, T.J. / Senger, S. / Stelman, G.J. / Toomey, J.R. / West, R.I. / Whittaker, C. / Zhou, P. / Young, R.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: The Discovery of Potent and Long-Acting Oral Factor Xa Inhibitors with Tetrahydroisoquinoline and Benzazepine P4 Motifs.
Authors: Watson, N.S. / Adams, C. / Belton, D. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Harling, J.D. / Irvine, S. / Irving, W.R. / ...Authors: Watson, N.S. / Adams, C. / Belton, D. / Brown, D. / Burns-Kurtis, C.L. / Chaudry, L. / Chan, C. / Convery, M.A. / Davies, D.E. / Exall, A.M. / Harling, J.D. / Irvine, S. / Irving, W.R. / Kleanthous, S. / Mclay, I.M. / Pateman, A.J. / Patikis, A.N. / Roethke, T.J. / Senger, S. / Stelman, G.J. / Toomey, J.R. / West, R.I. / Whittaker, C. / Zhou, P. / Young, R.J.
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 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_entry_details.has_protein_modification / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_ptnr2_PDB_ins_code / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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

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)44,3005
Polymers43,7612
Non-polymers5383
Water4,414245
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint-32.1 kcal/mol
Surface area13170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.859, 71.599, 78.279
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, 248 molecules

#3: Chemical ChemComp-MZA / 6-CHLORO-N-[(3S)-1-(5-FLUORO-1,2,3,4-TETRAHYDROISOQUINOLIN-6-YL)-2-OXO-PYRROLIDIN-3-YL]NAPHTHALENE-2-SULFONAMIDE


Mass: 473.948 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21ClFN3O3S
#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


Mass: 18.015 Da / Num. of mol.: 245 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsSEQUENCE 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: 2.23 Å3/Da / Density % sol: 44.39 % / Description: NONE
Crystal growpH: 5.75
Details: 16-20% PEG 6K, 50 MM MES PH 5.5-6, 5 MM CACL2, 50 MM NACL WITH SEEDING.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jun 28, 2005 / Details: OSMIC BLUE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→45.47 Å / Num. obs: 24069 / % possible obs: 94.8 % / Observed criterion σ(I): 0 / Redundancy: 3.82 % / Biso Wilson estimate: 31.034 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 16.8
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.81 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 4 / % possible all: 90.5

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.9→20 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.935 / SU B: 3.523 / SU ML: 0.103 / Cross valid method: THROUGHOUT / ESU R: 0.159 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. SOME RESIDUES IN CHAIN ARE NOT SEEN IN THE ELECTRON DENSITY.
RfactorNum. reflection% reflectionSelection details
Rfree0.22952 1230 5.1 %RANDOM
Rwork0.18555 ---
obs0.18772 22823 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: 44.182 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å20 Å20 Å2
2---0.54 Å20 Å2
3---0.35 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2228 0 34 245 2507
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222326
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4351.9643136
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0055284
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.57824.057106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.62515393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4741515
X-RAY DIFFRACTIONr_chiral_restr0.10.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211764
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_it1.20521421
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.24342268
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.9865905
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.4367868
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 86 -
Rwork0.272 1557 -
obs--100 %

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