5tks

FACTOR XIA IN COMPLEX WITH THE INHIBITOR ((15S)-18-CHLORO- 15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2- PROPENOYL)AMINO)-17,19-DIAZATRICYCLO[14.2.1.0~2,7~]NONADECA-1(18),2,4,6,16(19)-PENTAEN-5-YL)CARBAMATE

spinqualitylabelsall models 5tks, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tks is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.55Å Ligands: 7DL, EDO, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FA11_HUMAN Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:612416; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. Function FA11_HUMAN Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. Publication Abstract from PubMed A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 muM) and excellent selectivity against the relevant blood coagulation enzymes. Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.,Corte JR, Fang T, Osuna H, Pinto DJ, Rossi KA, Myers JE Jr, Sheriff S, Lou Z, Zheng JJ, Harper TW, Bozarth JM, Wu Y, Luettgen JM, Seiffert DA, Decicco CP, Wexler RR, Quan ML J Med Chem. 2017 Feb 9;60(3):1060-1075. doi: 10.1021/acs.jmedchem.6b01460. Epub, 2017 Jan 31. PMID:28085275 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Factor XIa 3D structures

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