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- PDB-2w3k: Crystal Structure of FXa in complex with 4,4-disubstituted pyrrol... -

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Basic information

Entry
Database: PDB / ID: 2w3k
TitleCrystal Structure of FXa in complex with 4,4-disubstituted pyrrolidine-1,2-dicarboxamide inhibitor 1
Components
  • COAGULATION FACTOR X, HEAVY CHAIN
  • COAGULATION FACTOR X, LIGHT CHAIN
KeywordsHYDROLASE / DRUG DESIGN / GLYCOPROTEIN / HYDROXYLATION / BLOOD CLOTTING / SERINE PROTEASE / EGF-LIKE DOMAIN / FXA COAGULATION FACTOR INHIBITOR / ZYMOGEN / PROTEASE / SECRETED / BLOOD COAGULATION / GAMMA-CARBOXYGLUTAMIC ACID / 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-L1D / Coagulation factor X
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsZhang, E. / Mochalkin, I. / Casimiro-Garcia, A. / Van Huis, C.A.
CitationJournal: Bioorg.Med.Chem. / Year: 2009
Title: Exploration of 4,4-Disubstituted Pyrrolidine-1,2-Dicarboxamides as Potent, Orally Active Factor Xa Inhibitors with Extended Duration of Action.
Authors: Van Huis, C.A. / Casimiro-Garcia, A. / Bigge, C.F. / Cody, W.L. / Dudley, D.A. / Filipski, K.J. / Heemstra, R.J. / Kohrt, J.T. / Leadley, R.J.J. / Narasimhan, L.S. / Mcclanahan, T. / ...Authors: Van Huis, C.A. / Casimiro-Garcia, A. / Bigge, C.F. / Cody, W.L. / Dudley, D.A. / Filipski, K.J. / Heemstra, R.J. / Kohrt, J.T. / Leadley, R.J.J. / Narasimhan, L.S. / Mcclanahan, T. / Mochalkin, I. / Pamment, M. / Peterson, J.T. / Sahasrabudhe, V. / Schaum, R.P. / Edmunds, J.J.
History
DepositionNov 12, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 7, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Sep 28, 2011Group: Atomic model / Derived calculations / Non-polymer description
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 / 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 / _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
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: COAGULATION FACTOR X, HEAVY CHAIN
B: COAGULATION FACTOR X, LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4944
Polymers31,9072
Non-polymers5872
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-11.6 kcal/mol
Surface area16090 Å2
MethodPQS
Unit cell
Length a, b, c (Å)56.359, 72.503, 78.399
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 COAGULATION FACTOR X, HEAVY CHAIN / ACTIVATED FACTOR XA / STUART FACTOR / STUART-PROWER FACTOR


Mass: 26447.104 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN, RESIDUES 235-468
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 COAGULATION FACTOR X, LIGHT CHAIN / ACTIVATED FACTOR XA / STUART FACTOR / STUART-PROWER FACTOR


Mass: 5460.055 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN, RESIDUES 128-178
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-L1D / (2R,4S)-N^1^-(4-chlorophenyl)-N^2^-[2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl]-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide


Mass: 546.977 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H24ClFN4O4
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.4 Å3/Da / Density % sol: 48.3 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Oct 10, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→20 Å / Num. obs: 19989 / % possible obs: 96.1 % / Observed criterion σ(I): 0 / Redundancy: 5.59 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 19.34
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 3.6 / % possible all: 83

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2PHB

2phb


Resolution: 2.05→50 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.93 / SU B: 9.107 / SU ML: 0.131 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.222 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.255 1032 5.2 %RANDOM
Rwork0.208 ---
obs0.211 18924 96.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.22 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---1.83 Å20 Å2
3---1.86 Å2
Refinement stepCycle: LAST / Resolution: 2.05→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2225 0 40 121 2386
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222317
X-RAY DIFFRACTIONr_bond_other_d0.0010.021598
X-RAY DIFFRACTIONr_angle_refined_deg1.2051.9663129
X-RAY DIFFRACTIONr_angle_other_deg0.8193.0083852
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0515279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8824.112107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.63815395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3271515
X-RAY DIFFRACTIONr_chiral_restr0.0720.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022578
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02473
X-RAY DIFFRACTIONr_nbd_refined0.2110.2448
X-RAY DIFFRACTIONr_nbd_other0.1880.21650
X-RAY DIFFRACTIONr_nbtor_refined0.1770.21114
X-RAY DIFFRACTIONr_nbtor_other0.0830.21253
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1270.2134
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2510.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2820.223
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1070.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5861.51453
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.97122248
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.21931004
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.8884.5881
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: 2.05→2.11 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 80 -
Rwork0.246 1220 -
obs--86.15 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.37580.06040.29943.0145-0.46871.5353-0.04430.05730.0569-0.0159-0.0209-0.3927-0.00050.09390.0653-0.09220.0027-0.0038-0.06680.0216-0.0361-18.4937-13.772523.6976
26.5355-2.6045-2.1084.85450.42942.77780.1490.47830.0466-0.09960.01370.3439-0.0372-0.3566-0.1627-0.0801-0.01760.0283-0.03630.0561-0.0855-41.5874-13.857529.6383
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A16 - 244
2X-RAY DIFFRACTION2B0 - 50

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