8r8e
DYRK1a in Complex with 2-Cyclopentyl-7-iodo-1H-indole-3-carbonitrile
Structural highlights
DiseaseDYR1A_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.[1] FunctionDYR1A_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.[2] Publication Abstract from PubMedHalogen bonding is a valuable interaction in drug design, offering an unconventional way to influence affinity and selectivity by leveraging the halogen atoms' ability to form directional bonds. The present study evaluates halogen-water interactions within protein binding sites, demonstrating that targeting a water molecule via halogen bonding can in specific cases contribute beneficially to ligand binding. In solving and examining the crystal structure of 2-cyclopentyl-7-iodo-1H-indole-3-carbonitrile bound to DYRK1a kinase, we identified a notable iodine-water interaction, where water accepts a halogen bond with good geometric and energetic features. This starting point triggered further investigations into the prevalence of such interactions across various halogen-bearing ligands (chlorine, bromine, iodine) in the PDB. Using QM calculations (MP2/TZVPP), we highlight the versatility and potential benefits of such halogen-water interactions, particularly when the water molecule is a stable part of the binding site's structured environment. While the interaction energies with water are lower compared to other typical halogen bond acceptors, we deem this different binding strength essential for reducing desolvation costs. We suggest that "interstitial" water molecules, as stable parts of the binding site engaging in multiple strong interactions, could be prime targets for halogen bonding. Further systematic studies, combining high-resolution crystal structures and quantum chemistry, are required to scrutinize whether halogen bonding on water is more than a "drop in the ocean". Halogen Bonding on Water horizontal line A Drop in the Ocean?,Engelhardt MU, Zimmermann MO, Dammann M, Stahlecker J, Poso A, Kronenberger T, Kunick C, Stehle T, Boeckler FM J Chem Theory Comput. 2024 Sep 18. doi: 10.1021/acs.jctc.4c00834. PMID:39291905[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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