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Yorodumi- PDB-6w50: FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((10R,14S)- 14-(4... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6w50 | ||||||
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Title | FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((10R,14S)- 14-(4-(3-CHLORO-2,6-DIFLUOROPHENYL)-6-OXO-3,6-DIHYDRO- 1(2H)-PYRIDINYL)-10-METHYL-9-OXO-8,16- DIAZATRICYCLO[13.3.1.0~2,7~]NONADECA-1(19),2,4,6,15,17- HEXAEN-5-YL)CARBAMATE | ||||||
Components | Coagulation factor XI | ||||||
Keywords | HYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / SERINE PROTEASE / BLOOD COAGULATION FACTOR / PROTEIN INHIBITOR COMPLEX / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
Function / homology | Function and homology information coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space ...coagulation factor XIa / serine-type aminopeptidase activity / Defective F9 activation / positive regulation of fibrinolysis / plasminogen activation / Intrinsic Pathway of Fibrin Clot Formation / blood coagulation / heparin binding / serine-type endopeptidase activity / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å | ||||||
Authors | Sheriff, S. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2020 Title: Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species. Authors: Yang, W. / Wang, Y. / Lai, A. / Clark, C.G. / Corte, J.R. / Fang, T. / Gilligan, P.J. / Jeon, Y. / Pabbisetty, K.B. / Rampulla, R.A. / Mathur, A. / Kaspady, M. / Neithnadka, P.R. / Arumugam, ...Authors: Yang, W. / Wang, Y. / Lai, A. / Clark, C.G. / Corte, J.R. / Fang, T. / Gilligan, P.J. / Jeon, Y. / Pabbisetty, K.B. / Rampulla, R.A. / Mathur, A. / Kaspady, M. / Neithnadka, P.R. / Arumugam, A. / Raju, S. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Chacko, S.A. / Bozarth, J.M. / Wu, Y. / Crain, E.J. / Wong, P.C. / Seiffert, D.A. / Luettgen, J.M. / Lam, P.Y.S. / Wexler, R.R. / Ewing, W.R. #1: Journal: J. Med. Chem. / Year: 2014 Title: Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors Authors: Quan, M.L. / Wong, P.C. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. ...Authors: Quan, M.L. / Wong, P.C. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. / Rendina, A.R. / Rossi, K.A. / Watson, C.A. / Wei, A. / Zhang, G. / Seiffert, D. / Wexler, R.R. #2: Journal: J. Med. Chem. / Year: 2014 Title: Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity. Authors: Quan, M.L. / Wong, P.C. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. ...Authors: Quan, M.L. / Wong, P.C. / Wang, C. / Woerner, F. / Smallheer, J.M. / Barbera, F.A. / Bozarth, J.M. / Brown, R.L. / Harpel, M.R. / Luettgen, J.M. / Morin, P.E. / Peterson, T. / Ramamurthy, V. / Rendina, A.R. / Rossi, K.A. / Watson, C.A. / Wei, A. / Zhang, G. / Seiffert, D. / Wexler, R.R. #3: Journal: J. Med. Chem. / Year: 2014 Title: Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity Authors: Hangeland, J.J. / Friends, T.J. / Rossi, K.A. / Smallheer, J.M. / Wang, C. / Sun, Z. / Corte, J.R. / Fang, T. / Wong, P.C. / Rendina, A.R. / Barbera, F.A. / Bozarth, J.M. / Luettgen, J.M. / ...Authors: Hangeland, J.J. / Friends, T.J. / Rossi, K.A. / Smallheer, J.M. / Wang, C. / Sun, Z. / Corte, J.R. / Fang, T. / Wong, P.C. / Rendina, A.R. / Barbera, F.A. / Bozarth, J.M. / Luettgen, J.M. / Watson, C.A. / Zhang, G. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Bisacchi, G.S. / Subramaniam, S. / Arunachalam, P. / Mathur, A. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L. #4: Journal: Bioorg. Med. Chem. Lett. / Year: 2015 Title: Pyridine and pyridinone-based factor XIa inhibitors. Authors: Corte, J.R. / Fang, T. / Hangeland, J.J. / Friends, T.J. / Rendina, A.R. / Luettgen, J.M. / Bozarth, J.M. / Barbera, F.A. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Seiffert, D. ...Authors: Corte, J.R. / Fang, T. / Hangeland, J.J. / Friends, T.J. / Rendina, A.R. / Luettgen, J.M. / Bozarth, J.M. / Barbera, F.A. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L. #5: Journal: Bioorg. Med. Chem. Lett. / Year: 2015 Title: Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Authors: Pinto, D.J. / Smallheer, J.M. / Corte, J.R. / Austin, E.J. / Wang, C. / Fang, T. / Smith II, L.M. / Rossi, K.A. / Rendina, A.R. / Bozarth, J.M. / Zhang, G. / Wei, A. / Ramamurthy, V. / ...Authors: Pinto, D.J. / Smallheer, J.M. / Corte, J.R. / Austin, E.J. / Wang, C. / Fang, T. / Smith II, L.M. / Rossi, K.A. / Rendina, A.R. / Bozarth, J.M. / Zhang, G. / Wei, A. / Ramamurthy, V. / Sheriff, S. / Myers Jr., J.E. / Morin, P.E. / Luettgen, J.M. / Seiffert, D.A. / Quan, M.L. / Wexler, R.R. #6: Journal: ACS Med Chem Lett / Year: 2015 Title: Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety. Authors: Hu, Z. / Wong, P.C. / Gilligan, P.J. / Han, W. / Pabbisetty, K.B. / Bozarth, J.M. / Crain, E.J. / Harper, T. / Luettgen, J.M. / Myers Jr., J.E. / Ramamurthy, V. / Rossi, K.A. / Sheriff, S. / ...Authors: Hu, Z. / Wong, P.C. / Gilligan, P.J. / Han, W. / Pabbisetty, K.B. / Bozarth, J.M. / Crain, E.J. / Harper, T. / Luettgen, J.M. / Myers Jr., J.E. / Ramamurthy, V. / Rossi, K.A. / Sheriff, S. / Watson, C.A. / Wei, A. / Zheng, J.J. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L. #7: Journal: Bioorg. Med. Chem. Lett. / Year: 2016 Title: Novel phenylalanine derived diamides as Factor XIa inhibitors. Authors: Smith II, L.M. / Orwat, M.J. / Hu, Z. / Han, W. / Wang, C. / Rossi, K.A. / Gilligan, P.J. / Pabbisetty, K.B. / Osuna, H. / Corte, J.R. / Rendina, A.R. / Luettgen, J.M. / Wong, P.C. / ...Authors: Smith II, L.M. / Orwat, M.J. / Hu, Z. / Han, W. / Wang, C. / Rossi, K.A. / Gilligan, P.J. / Pabbisetty, K.B. / Osuna, H. / Corte, J.R. / Rendina, A.R. / Luettgen, J.M. / Wong, P.C. / Narayanan, R. / Harper, T.W. / Bozarth, J.M. / Crain, E.J. / Wei, A. / Ramamurthy, V. / Morin, P.E. / Xin, B. / Zheng, J. / Seiffert, D.A. / Quan, M.L. / Lam, P.Y.S. / Wexler, R.R. / Pinto, D.J.P. #8: Journal: Bioorg. Med. Chem. / Year: 2016 Title: Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group. Authors: Corte, J.R. / Fang, T. / Pinto, D.J. / Orwat, M.J. / Rendina, A.R. / Luettgen, J.M. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Myers Jr., J.E. / Sheriff, S. / Narayanan, R. / Harper, T.W. / ...Authors: Corte, J.R. / Fang, T. / Pinto, D.J. / Orwat, M.J. / Rendina, A.R. / Luettgen, J.M. / Rossi, K.A. / Wei, A. / Ramamurthy, V. / Myers Jr., J.E. / Sheriff, S. / Narayanan, R. / Harper, T.W. / Zheng, J.J. / Li, Y.X. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L. #9: Journal: J. Med. Chem. / Year: 2017 Title: Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker. Authors: Corte, J.R. / Fang, T. / Osuna, H. / Pinto, D.J. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D. ...Authors: Corte, J.R. / Fang, T. / Osuna, H. / Pinto, D.J. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / Decicco, C.P. / Wexler, R.R. / Quan, M.L. #10: Journal: Bioorg. Med. Chem. Lett. / Year: 2017 Title: Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency. Authors: Corte, J.R. / Yang, W. / Fang, T. / Wang, Y. / Osuna, H. / Lai, A. / Ewing, W.R. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. ...Authors: Corte, J.R. / Yang, W. / Fang, T. / Wang, Y. / Osuna, H. / Lai, A. / Ewing, W.R. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / Quan, M.L. / Wexler, R.R. / Lam, P.Y.S. #11: Journal: Bioorg. Med. Chem. Lett. / Year: 2017 Title: Macrocyclic factor XIa inhibitors. Authors: Wang, C. / Corte, J.R. / Rossi, K.A. / Bozarth, J.M. / Wu, Y. / Sheriff, S. / Myers Jr., J.E. / Luettgen, J.M. / Seiffert, D.A. / Wexler, R.R. / Quan, M.L. #12: Journal: J. Med. Chem. / Year: 2017 Title: Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212). Authors: Pinto, D.J.P. / Orwat, M.J. / Smith II, L.M. / Quan, M.L. / Lam, P.Y.S. / Rossi, K.A. / Apedo, A. / Bozarth, J.M. / Wu, Y. / Zheng, J.J. / Xin, B. / Toussaint, N. / Stetsko, P. / ...Authors: Pinto, D.J.P. / Orwat, M.J. / Smith II, L.M. / Quan, M.L. / Lam, P.Y.S. / Rossi, K.A. / Apedo, A. / Bozarth, J.M. / Wu, Y. / Zheng, J.J. / Xin, B. / Toussaint, N. / Stetsko, P. / Gudmundsson, O. / Maxwell, B. / Crain, E.J. / Wong, P.C. / Lou, Z. / Harper, T.W. / Chacko, S.A. / Myers Jr., J.E. / Sheriff, S. / Zhang, H. / Hou, X. / Mathur, A. / Seiffert, D.A. / Wexler, R.R. / Luettgen, J.M. / Ewing, W.R. #13: Journal: Bioorg. Med. Chem. Lett. / Year: 2019 Title: Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability. Authors: Clark, C.G. / Rossi, K.A. / Corte, J.R. / Fang, T. / Smallheer, J.M. / De Lucca, I. / Nirschl, D.S. / Orwat, M.J. / Pinto, D.J.P. / Hu, Z. / Wang, Y. / Yang, W. / Jeon, Y. / Ewing, W.R. / ...Authors: Clark, C.G. / Rossi, K.A. / Corte, J.R. / Fang, T. / Smallheer, J.M. / De Lucca, I. / Nirschl, D.S. / Orwat, M.J. / Pinto, D.J.P. / Hu, Z. / Wang, Y. / Yang, W. / Jeon, Y. / Ewing, W.R. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Bozarth, J.M. / Wu, Y. / Rendina, A. / Harper, T. / Zheng, J. / Xin, B. / Xiang, Q. / Leuttgen, J.M. / Seiffert, D.A. / Wexler, R.R. / Lam, P.Y.S. #14: Journal: J. Med. Chem. / Year: 2019 Title: Potent, Orally Bioavailable and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups. Authors: Corte, J.R. / Pinto, D.J.P. / Fang, T. / Osuna, H. / Yang, W. / Wang, Y. / Lai, A. / Clark, C.G. / Sun, J.-H. / Rampulla, R. / Mathur, A. / Kaspady, M. / Neithnadka, P.R. / Li, Y.-X.C. / ...Authors: Corte, J.R. / Pinto, D.J.P. / Fang, T. / Osuna, H. / Yang, W. / Wang, Y. / Lai, A. / Clark, C.G. / Sun, J.-H. / Rampulla, R. / Mathur, A. / Kaspady, M. / Neithnadka, P.R. / Li, Y.-X.C. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Harper, T.W. / Huang, C. / Zheng, J.J. / Bozarth, J.M. / Wu, Y. / Wong, P.C. / Crain, E.J. / Seiffert, D.A. / Luettgen, J.M. / Lam, P.Y.S. / Wexler, R.R. / Ewing, W.R. #15: Journal: Bioorg. Med. Chem. Lett. / Year: 2020 Title: Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa. Authors: Fang, T. / Corte, J.R. / Gilligan, P.J. / Jeon, Y. / Osuna, H. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. ...Authors: Fang, T. / Corte, J.R. / Gilligan, P.J. / Jeon, Y. / Osuna, H. / Rossi, K.A. / Myers Jr., J.E. / Sheriff, S. / Lou, Z. / Zheng, J.J. / Harper, T.W. / Bozarth, J.M. / Wu, Y. / Luettgen, J.M. / Seiffert, D.A. / Wexler, R.R. / Lam, P.Y.S. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6w50.cif.gz | 77.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6w50.ent.gz | 54.5 KB | Display | PDB format |
PDBx/mmJSON format | 6w50.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6w50_validation.pdf.gz | 762 KB | Display | wwPDB validaton report |
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Full document | 6w50_full_validation.pdf.gz | 762.9 KB | Display | |
Data in XML | 6w50_validation.xml.gz | 14.3 KB | Display | |
Data in CIF | 6w50_validation.cif.gz | 21.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w5/6w50 ftp://data.pdbj.org/pub/pdb/validation_reports/w5/6w50 | HTTPS FTP |
-Related structure data
Related structure data | 4ty7S S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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Components on special symmetry positions |
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-Components
#1: Protein | Mass: 27600.342 Da / Num. of mol.: 1 / Fragment: COAGULATION FACTOR XI, HEAVY CHAIN Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: F11 / Plasmid: PET14B / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03951, coagulation factor XIa | ||||||
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#2: Chemical | ChemComp-SWP / | ||||||
#3: Chemical | #4: Chemical | ChemComp-EDO / #5: Water | ChemComp-HOH / | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.47 Å3/Da / Density % sol: 64.53 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 Details: 100 mM sodium acetate, pH 4.6, 25% (w/v) MePEG2000, 200 mM ammonium sulfate, then transferred to 100 mM Tris-HCl, pH 7.0, 25% (w/v) MePEG2000, 200 MM ammonium sulfate |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 29, 2012 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.95→35.54 Å / Num. obs: 28492 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 9.7 % / Biso Wilson estimate: 27.53 Å2 / Rsym value: 0.076 / Net I/σ(I): 22.2 |
Reflection shell | Resolution: 1.95→2.06 Å / Redundancy: 9.7 % / Mean I/σ(I) obs: 5 / Num. unique obs: 4073 / Rsym value: 0.497 / % possible all: 100 |
-Phasing
Phasing | Method: molecular replacement |
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4TY7 Resolution: 1.95→35.54 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.951 / SU R Cruickshank DPI: 0.101 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.109 / SU Rfree Blow DPI: 0.098 / SU Rfree Cruickshank DPI: 0.093
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Displacement parameters | Biso max: 110.47 Å2 / Biso mean: 30.53 Å2 / Biso min: 13.89 Å2
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Refine analyze | Luzzati coordinate error obs: 0.21 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.95→35.54 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.95→2.02 Å / Total num. of bins used: 14
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