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- PDB-2vwl: Aminopyrrolidine Factor Xa inhibitor -

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Basic information

Entry
Database: PDB / ID: 2vwl
TitleAminopyrrolidine Factor Xa inhibitor
Components
  • ACTIVATED FACTOR XA HEAVY CHAIN
  • FACTOR X LIGHT CHAIN
KeywordsBLOOD CLOTTING / HYDROLASE / CATION / PLASMA / CALCIUM / ZYMOGEN / PROTEASE / INHIBITOR / POLYMORPHISM / GLYCOPROTEIN / GAMMA-CARBOXYGLUTAMIC ACID / COAGULATION FACTOR / HYDROXYLATION / SERINE PROTEASE / EGF-LIKE DOMAIN / CLEAVAGE ON PAIR OF BASIC RESIDUES
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-LZH / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsGroebke-Zbinden, K. / Banner, D.W. / Benz, J.M. / Blasco, F. / Decoret, G. / Himber, J. / Kuhn, B. / Panday, N. / Ricklin, F. / Risch, P. ...Groebke-Zbinden, K. / Banner, D.W. / Benz, J.M. / Blasco, F. / Decoret, G. / Himber, J. / Kuhn, B. / Panday, N. / Ricklin, F. / Risch, P. / Schlatter, D. / Stahl, M. / Unger, R. / Haap, W.
CitationJournal: Eur.J.Med.Chem. / Year: 2009
Title: Design of Novel Aminopyrrolidine Factor Xa Inhibitors from a Screening Hit.
Authors: Zbinden, K.G. / Anselm, L. / Banner, D.W. / Benz, J.M. / Blasco, F. / Decoret, G. / Himber, J. / Kuhn, B. / Panday, N. / Ricklin, F. / Risch, P. / Schlatter, D. / Stahl, M. / Thomi, S. / Unger, R. / Haap, W.
History
DepositionJun 26, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / 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_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_alt_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_alt_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_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_PDB_ins_code / _struct_conn.pdbx_ptnr2_label_alt_id / _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
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-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
L: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8376
Polymers33,2342
Non-polymers6034
Water4,792266
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-13.1 kcal/mol
Surface area15180 Å2
MethodPQS
2
A: ACTIVATED FACTOR XA HEAVY CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7765
Polymers27,1731
Non-polymers6034
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
L: FACTOR X LIGHT CHAIN


Theoretical massNumber of molelcules
Total (without water)6,0611
Polymers6,0611
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.800, 105.800, 49.720
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 2 types, 2 molecules AL

#1: Protein ACTIVATED FACTOR XA HEAVY CHAIN


Mass: 27172.980 Da / Num. of mol.: 1 / Fragment: PEPTIDASE S1, RESIDUES 235-475 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00742, coagulation factor Xa
#2: Protein FACTOR X LIGHT CHAIN


Mass: 6060.816 Da / Num. of mol.: 1 / Fragment: EGF2, RESIDUES 126-180
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00742, coagulation factor Xa

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Non-polymers , 5 types, 270 molecules

#3: Chemical ChemComp-LZH / 5-CHLORO-THIOPHENE-2-CARBOXYLIC ACID ((3R,5S)-1-{[2-FLUORO-4-(2-OXO-PYRIDIN-1-YL)-PHENYLCARBAMOYL]-METHYL}-5-HYDROXYMETHYL-PYRROLIDIN-3-YL)-AMIDE


Mass: 504.962 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22ClFN4O4S
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 372 TO GLU
Has protein modificationY
Sequence detailsARG-GLU MUTANT.THE RESIDUE NUMBERING IN THE CATALYTIC DOMAIN FOLLOWS THAT OF CHYMOTRYPSINOGEN

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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: 44.8 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.980103
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 27, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.980103 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 26527 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 5.74 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 16.92
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 5.73 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 3.6 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.4.0067refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2VVC

2vvc


Resolution: 1.8→74.74 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.917 / SU B: 3.296 / SU ML: 0.103 / Cross valid method: THROUGHOUT / ESU R: 0.144 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE NOT BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25 1332 5 %RANDOM
Rwork0.194 ---
obs0.197 25195 99.2 %-
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: 29.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---0.02 Å20 Å2
3---0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.8→74.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2160 0 37 266 2463
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222290
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4641.9663087
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6035281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.35624.175103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.60315391
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5931514
X-RAY DIFFRACTIONr_chiral_restr0.1280.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211740
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_it0.8681.51397
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.47622237
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.0543893
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2784.5850
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: 1.8→1.85 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.303 95
Rwork0.251 1842

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