7zh8 | pdb_00007zh8

DYRK1a in Complex with a Bromo-Triazolo-Pyridine

spinqualitylabelsall models 7zh8, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7zh8 is a 4 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 2.3Å Ligands: 1PE, CL, EPE, GOL, IWU, PEG, PG4, PGE, PTR, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DYR1A_HUMAN Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Function DYR1A_HUMAN May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates. Publication Abstract from PubMed We conceived the Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in the early stages of drug discovery. As the number of competitive interactions increases with ligand size, we reasoned that a binding mode relying on halogen bonding is more likely for fragments than highly decorated molecules. Thus, fragments could feature unexplored binding modes. We screened the HEFLib against the human kinase DYRK1a and verified micromolar binding fragments via isothermal titration calorimetry (ITC). The crystal structure of one fragment revealed a noncanonical binding mode, despite the fragment's classical hinge binding motif. In addition, the fragment occupies a secondary binding site. Both binding modes feature a halogen bond, which we evaluated by ab initio calculations. Structure-affinity relationship (SAR) from a set of analogues improves the affinity, provides a promising fragment-growth vector, and highlights the benefits and applicability of halogen bonds in early lead development. Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.,Dammann M, Stahlecker J, Zimmermann MO, Klett T, Rotzinger K, Kramer M, Coles M, Stehle T, Boeckler FM J Med Chem. 2022 Nov 10;65(21):14539-14552. doi: 10.1021/acs.jmedchem.2c00951. , Epub 2022 Oct 26. PMID:36288453 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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