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- PDB-2vwm: Aminopyrrolidine Factor Xa inhibitor -

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Basic information

Entry
Database: PDB / ID: 2vwm
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-LZI / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.96 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 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Dec 13, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / 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_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_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _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_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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 1.5Nov 6, 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. THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BA" 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. THE SHEETS PRESENTED AS "BB" 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: ACTIVATED FACTOR XA HEAVY CHAIN
K: FACTOR X LIGHT CHAIN
L: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6588
Polymers66,4684
Non-polymers1,1904
Water10,106561
1
A: ACTIVATED FACTOR XA HEAVY CHAIN
L: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8294
Polymers33,2342
Non-polymers5952
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-12.9 kcal/mol
Surface area16030 Å2
MethodPQS
2
B: ACTIVATED FACTOR XA HEAVY CHAIN
K: FACTOR X LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8294
Polymers33,2342
Non-polymers5952
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1970 Å2
ΔGint-11.2 kcal/mol
Surface area16270 Å2
MethodPQS
3
A: ACTIVATED FACTOR XA HEAVY CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7683
Polymers27,1731
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
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
5
B: ACTIVATED FACTOR XA HEAVY CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7683
Polymers27,1731
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
K: 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)48.930, 77.110, 74.870
Angle α, β, γ (deg.)90.00, 92.07, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein ACTIVATED FACTOR XA HEAVY CHAIN


Mass: 27172.980 Da / Num. of mol.: 2 / Fragment: PEPTIDASE S1 DOMAIN, 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.: 2 / 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
#3: Chemical ChemComp-LZI / (4R)-4-{[(5-chlorothiophen-2-yl)carbonyl]amino}-N-(cyclopropylmethyl)-1-(2-{[2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl]amino}-2-oxoethyl)-L-prolinamide


Mass: 572.051 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27ClFN5O4S
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 561 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 372 TO GLU ENGINEERED RESIDUE IN CHAIN B, ARG 372 TO GLU
Has protein modificationY
Nonpolymer detailsHETGROUP LZI : THE CYCLOPROPYL-METHYL GROUP OF THE INHIBITOR HAS NO ELECTRON DENSITY.THE AMIDE ...HETGROUP LZI : THE CYCLOPROPYL-METHYL GROUP OF THE INHIBITOR HAS NO ELECTRON DENSITY.THE AMIDE LINKAGE MAY HAVE BEEN HYDROLYSED TO LEAVE THE FREE ACID.
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: 2.25 Å3/Da / Density % sol: 45.3 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jan 19, 2005 / Details: OSMICS
RadiationMonochromator: OSMICS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.96→50 Å / Num. obs: 36648 / % possible obs: 91.6 % / Observed criterion σ(I): -3 / Redundancy: 4.01 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 20.7
Reflection shellResolution: 1.96→2.07 Å / Redundancy: 3.93 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 6.57 / % possible all: 99.6

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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: 1.96→74.74 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.889 / SU B: 5.249 / SU ML: 0.153 / Cross valid method: THROUGHOUT / ESU R: 0.244 / ESU R Free: 0.214 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.273 1839 5 %RANDOM
Rwork0.2 ---
obs0.204 34816 91.7 %-
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: 30.68 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å20 Å2-0.19 Å2
2--0.76 Å20 Å2
3----0.47 Å2
Refinement stepCycle: LAST / Resolution: 1.96→74.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4389 0 80 561 5030
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224652
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.511.9666293
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.845574
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.40723.876209
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.1915797
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5431531
X-RAY DIFFRACTIONr_chiral_restr0.0920.2665
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213549
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_it0.8321.52828
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.45524551
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.88431824
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8794.51742
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: 1.96→2.01 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.352 139
Rwork0.233 2730

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