9BYJ

Crystal Structure of Hck in complex with the Src-family kinase inhibitor A-419259

Summary for 9BYJ

• Entry DOI: 10.2210/pdb9byj/pdb
• Descriptor: Tyrosine-protein kinase HCK, 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: src family kinase, inhibitor, transferase inhibitor, tyrosine kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 54169.02

Authors

Selzer, A.M.,Alvarado, J.J.,Smithgall, T.E. (deposition date: 2024-05-23, release date: 2024-10-09, Last modification date: 2024-10-30)

Primary citation

Selzer, A.M.,Alvarado, J.J.,Smithgall, T.E.
Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation.
Biochemistry, 63:2594-2601, 2024

PubMed Abstract: Hematopoietic cell kinase (Hck) is a member of the Src kinase family and is a promising drug target in myeloid leukemias. Here, we report the crystal structure of human Hck in complex with the pyrrolopyrimidine inhibitor A-419259, determined at a resolution of 1.8 Å. This structure reveals the complete Hck active site in the presence of A-419259, including the αC-helix, the DFG motif, and the activation loop. A-419259 binds at the ATP-site of Hck and induces an overall closed conformation of the kinase with the regulatory SH3 and SH2 domains bound intramolecularly to their respective internal ligands. A-419259 stabilizes the DFG-in/αC-helix-out conformation observed previously with Hck and the pyrazolopyrimidine inhibitor PP1 (PDB: 1QCF). However, the activation loop conformations are distinct, with PP1 inducing a folded loop structure with the tyrosine autophosphorylation site (Tyr416) pointing into the ATP binding site, while A-419259 stabilizes an extended loop conformation with Tyr416 facing out into the solvent. Autophosphorylation also induces activation loop extension and significantly reduces the Hck sensitivity to PP1 but not A-419259. In cancer cells where Hck is constitutively active, the extended autophosphorylation loop may render Hck more sensitive to inhibitors like A-419259 which prefer this kinase conformation. More generally, these results provide additional insight into targeted kinase inhibitor design and how conformational preferences of inhibitors may impact selectivity and potency.

PubMed: 39315638
DOI: 10.1021/acs.biochem.4c00323

Experimental method

X-RAY DIFFRACTION (1.8 Å)