9Z6D

Crystal structure of LIMK1 mutant D460N bound to small molecule inhibitor cLIMK1i

This is a non-PDB format compatible entry.

Summary for 9Z6D

• Entry DOI: 10.2210/pdb9z6d/pdb
• Descriptor: LIM domain kinase 1, N-(3'-methyl-5'-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}[1,1'-biphenyl]-4-yl)prop-2-enamide (3 entities in total)
• Functional Keywords: kinase, climk1i, inhibitor, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73310.93

Authors

Patteson, J.,Manolaridis, I.,Gabelli, S.B.,Bukhtiyarova, M. (deposition date: 2025-11-14, release date: 2026-07-29)

Primary citation

Patteson, J.B.,Manolaridis, I.,Hong, M.R.,Johnston, J.M.,Mesbahi-Vasey, S.,Gregory, M.C.,Iwamoto, D.V.,Reid, J.C.,Sanders, J.M.,Lovatt, D.,McDonald, T.P.,Shurtleff, V.W.,Gabelli, S.B.,Bukhtiyarova, M.
A covalent inhibitor targeting Cys-349 of LIMK1 confers selectivity over LIMK2.
J.Biol.Chem., :113322-113322, 2026

PubMed Abstract: LIM domain kinase 1 (LIMK1) has been identified as a promising therapeutic target for a variety of conditions, such as chronic pain, open-angle glaucoma, various cancers, schizophrenia, and Fragile X syndrome. However, identifying inhibitors that selectively inhibit LIMK1 over LIM domain kinase 2 (LIMK2) has proven to be challenging. A viable strategy to overcome this difficulty is the development of covalent inhibitors, which can offer both potency and selectivity for LIMK1 due to a reactive cysteine, C349, near the active site absent in its paralog LIMK2. Here we identify an irreversible covalent inhibitor of LIMK1 (cLIMK1i), which is highly selective for LIMK1 over both LIMK2 and a panel of over 100 kinases. A crystal structure of LIMK1 soaked with cLIMK1i reveals it is a type I inhibitor occupying the ATP-binding site with its acrylamide moiety oriented toward the P-loop where C349 resides. Computational modeling supports that the P-loop of LIMK1 can adopt a conformation compatible with covalent bond formation. Biochemical and biophysical characterization of the interaction of cLIMK1i with LIMK1 demonstrates that the covalent bond with LIMK1-C349 is essential for its potent inhibition. These results support covalent inhibition of LIMK1 as a viable strategy for selectively inhibiting LIMK1 over LIMK2 and other kinases.

PubMed: 42442493
DOI: 10.1016/j.jbc.2026.113322

Experimental method

X-RAY DIFFRACTION (1.94 Å)