13LXSummary for 13LX
| Entry DOI | 10.2210/pdb13lx/pdb |
| Descriptor | Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, (4R)-1-cyclopentyl-4-(3-hydroxyphenyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (3 entities in total) |
| Functional Keywords | kinase, pkmyt1, inhibitor, allosteric, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32535.04 |
| Authors | |
| Primary citation | Herrington, N.B.,Khamrui, S.,Zhao, Y.,Lansiquot, C.,Wu, R.,Pandey, G.,Lazarus, M.B.,Schlessinger, A. Allosteric Inhibition of PKMYT1 Induces a Unique, Inactive ATP Binding Site Conformation. J.Am.Chem.Soc., 2026 Cited by PubMed Abstract: The protein kinase PKMYT1 regulates a key cell cycle checkpoint as part of the cell's DNA-damage repair response, but in cancer, this function can promote tumor cell survival through avoiding mitotic catastrophe. PKMYT1 has been linked to a variety of cancer types, including breast, gastric, and nonsmall cell lung cancers, as well as kidney renal clear cell carcinoma, making it an important therapeutic target. However, potent and selective small-molecule inhibitors of PKMYT1 are scarce, and its specific biological role in tumor proliferation remains understudied. Here, we report the discovery and characterization of a novel PKMYT1 inhibitor, , bound to a previously unknown allosteric site. Structural and kinetic data reveal that induces a conformational rearrangement of the P-loop and inhibits PKMYT1 through a mixed ATP competitive and noncompetitive mechanism. A closely related analogue, , exhibits selectivity and enhanced potency and engages PKMYT1 in cells. Surprisingly, however, it binds in the ATP binding pocket, demonstrating that subtle chemical modifications can shift binding mode and mechanism of inhibition. Furthermore, computational analysis using structural modeling methods, including AlphaFold2, AlphaFold3, Boltz-2, as well as unbiased MD simulations, indicates that these approaches are limited in their ability to capture this inhibitor-induced cryptic binding site and conformational change. Our study identifies an underexplored allosteric site in PKMYT1 and establishes a new avenue for the rational design of selective kinase inhibitors targeting a cryptic binding site in this emerging drug target. These findings also reveal intrinsic challenges in the computational discovery of noncanonical kinase binding sites and underscore the necessity of integrating computational modeling with experimental testing using structural and functional approaches. PubMed: 42227652DOI: 10.1021/jacs.6c05178 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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