24WC
Crystal structure of Haspin (GSG2) with an ATP-mimicking inhibitor LJ-5242
This is a non-PDB format compatible entry.
Summary for 24WC
| Entry DOI | 10.2210/pdb24wc/pdb |
| Descriptor | Serine/threonine-protein kinase haspin, 4-azanyl-7-[(2~{R},3~{R},4~{S},5~{R})-3,4-bis(oxidanyl)-5-[(sulfamoylamino)methyl]thiolan-2-yl]-5-ethynyl-pyrrolo[2,3-d]pyrimidine (3 entities in total) |
| Functional Keywords | serine/threonine-protein kinase haspin, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 39270.91 |
| Authors | |
| Primary citation | Cheon, S.W.,Yum, Y.A.,Ku, D.,Jang, S.C.,Aswar, V.R.,Jarhad, D.B.,Heo, Y.,Kim, H.S.,Lee, S.K.,Jeong, L.S.,Han, B.W. Structural insights into selective recognition of ATP-mimicking inhibitors by the atypical kinase HASPIN. Sci Rep, 2026 Cited by PubMed Abstract: Achieving 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 Å and 1.88 Å, 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 αC 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. PubMed: 42289584DOI: 10.1038/s41598-026-57282-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.88 Å) |
Structure validation
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