24wc
Crystal structure of Haspin (GSG2) with an ATP-mimicking inhibitor LJ-5242
Structural highlights
FunctionHASP_HUMAN Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.[1] [2] [3] [4] [5] Publication Abstract from PubMedAchieving selectivity among ATP-competitive kinase inhibitors remains a major challenge due to the high conservation of the ATP-binding pocket across the kinome. Although most kinase inhibitors target the ATP-binding site, ATP-mimicking compounds remain relatively uncommon due to concerns regarding selectivity. Here, we report the structural and biophysical characterization of the atypical serine/threonine kinase haploid germ cell-specific nuclear protein kinase (HASPIN) with two ATP-mimicking inhibitors, LJ-5157 and LJ-5242. Crystal structures of HASPIN in complex with LJ-5157 and with LJ-5242 were determined at resolutions of 1.74 A and 1.88 A, respectively, revealing ATP-like binding modes within the catalytic pocket. Structural analysis showed that the regulatory and catalytic spines of HASPIN are preorganized through extensive hydrophobic packing, particularly within the N-lobe, stabilizing the alphaC helix independently of nucleotide binding. Despite similar binding modes, microscale thermophoresis measurements demonstrated that LJ-5242 binds ~ 10-fold more tightly than LJ-5157. LJ-5157 and LJ-5242 exhibited selective HASPIN inhibition, with LJ-5242 showing ~ 10-fold and ~ 100-fold higher potency and selectivity in kinase inhibition and antiproliferative activity assays, respectively. These findings demonstrate that the distinctive architecture of the HASPIN ATP-binding pocket enables selective recognition of ATP-mimicking inhibitors and provides a framework for designing kinase inhibitors that retain ATP-like scaffolds while achieving selectivity. Structural insights into selective recognition of ATP-mimicking inhibitors by the atypical kinase HASPIN.,Cheon SW, Yum YA, Ku D, Jang SC, Aswar VR, Jarhad DB, Heo Y, Kim HS, Lee SK, Jeong LS, Han BW Sci Rep. 2026 Jun 14. doi: 10.1038/s41598-026-57282-y. PMID:42289584[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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