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ATP-competitive inhibitors that demonstrate exquisite selectivity for specific members of the human kinome have been developed. Despite this success, the identification of highly selective inhibitors is still very challenging and it is often not possible to rationally engineer selectivity between the ATP-binding sites of kinases, especially amongst closely-related family members. Src-family kinases (SFKs) are a highly homologous family of eight multi-domain, non-receptor tyrosine kinases that play general and specialized roles in numerous cellular processes. The high sequence and functional similarities between SFK members make it hard to rationalize how selectivity can be gained with inhibitors that target the ATP-binding site. Here, we describe the development of a series of inhibitors that are highly selective for the ATP-binding sites of the SFKs Lyn and Hck over other SFKs. By biochemically characterizing how these selective ATP-competitive inhibitors allosterically influence the global conformation of SFKs, we demonstrate that they most likely interact with a binding pocket created by the movement of the conformationally-flexible helix C in the ATP-binding site. With a series of sequence swap experiments, we show that sensitivity to this class of selective inhibitors is due to the identity of residues that control the conformational flexibility of helix C rather than any specific ATP-binding site interactions. Thus, the ATP-binding sites of highly homologous kinases can be discriminated by targeting heterogeneity within conformationally flexible regions.
This article was published in the following journal.
Name: ACS chemical biology
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The small ribonucleoprotein component of RIBOSOMES. It contains the MESSENGER RNA binding site and two TRANSFER RNA binding sites - one for the incoming AMINO ACYL TRNA (A site) and the other (P site) for the peptidyl tRNA carrying the elongating peptide chain.
A site on an enzyme which upon binding of a modulator, causes the enzyme to undergo a conformational change that may alter its catalytic or binding properties.
The largest of the three prokaryotic initiation factors with a molecular size of approximately 80 kD. It functions in the transcription initiation process by promoting the binding of formylmethionine-tRNA to the P-site of the 30S ribosome and by preventing the incorrect binding of elongator tRNA to the translation initiation site.
A prokaryotic ATP-dependent protease that plays a role in the degradation of many abnormal proteins. It is a tetramer of 87-kDa subunits, each of which contains a proteolytic site and a ATP-binding site.
The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.
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