4MCV

Star 12 bound to analog-sensitive Src kinase

Summary for 4MCV

• Entry DOI: 10.2210/pdb4mcv/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, (7S)-12-(4-aminobutyl)-7-(2-methylpropyl)-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one (2 entities in total)
• Functional Keywords: kinase domain, tyrosine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Gallus gallus (bantam,chickens)
• Cellular location: Cell membrane : P00523
• Total number of polymer chains: 2
• Total formula weight: 64534.39

Authors

Lopez, M.S.,Shokat, K.M. (deposition date: 2013-08-21, release date: 2013-11-20, Last modification date: 2024-02-28)

Primary citation

Lopez, M.S.,Choy, J.W.,Peters, U.,Sos, M.L.,Morgan, D.O.,Shokat, K.M.
Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology.
J.Am.Chem.Soc., 135:18153-18159, 2013

PubMed Abstract: Analog-sensitive (AS) kinase technology is a powerful approach for studying phospho-signaling pathways in diverse organisms and physiological processes. The key feature of this technique is that a kinase-of-interest can be mutated to sensitize it to inhibitor analogs that do not target wild-type (WT) kinases. In theory, this enables specific inhibition of any kinase in cells and in mouse models of human disease. Typically, these inhibitors are identified from a small library of molecules based on the pyrazolopyrimidine (PP) scaffold. However, we recently identified a subset of native human kinases, including the Ephrin A kinase family, that are sensitive to commonly used PP inhibitors. In an effort to develop a bioorthogonal AS-kinase inhibitor and to extend this technique to PP-sensitive kinases, we sought an alternative inhibitor scaffold. Here we report the structure-based design of synthetically tractable, potent, and extremely selective AS-kinase inhibitors based on the natural product staurosporine. We demonstrate that these molecules, termed staralogs, potently target AS kinases in cells, and we employ X-ray crystallography to elucidate their mechanism of efficacy. Finally, we demonstrate that staralogs target AS mutants of PP-sensitive kinases at concentrations where there is little to no inhibition of native human kinases. Thus, staralogs represent a new class of AS-kinase inhibitors and a core component of the chemical genetic tool kit for probing kinase-signaling pathways.

PubMed: 24171479
DOI: 10.1021/ja408704u

Experimental method

X-RAY DIFFRACTION (2.73 Å)