3F6X

c-Src kinase domain in complex with small molecule inhibitor

Summary for 3F6X

• Entry DOI: 10.2210/pdb3f6x/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, [4-({4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl}amino)phenyl]acetonitrile (3 entities in total)
• Functional Keywords: kinase, atp-binding, alternative splicing, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• Biological source: Gallus gallus (bantam,chickens)
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 4
• Total formula weight: 132432.31

Authors

Seeliger, M.A.,Statsuk, A.V.,Maly, D.J.,Patrick, P.Z.,Kuriyan, J.,Shokat, K.M. (deposition date: 2008-11-06, release date: 2008-12-09, Last modification date: 2023-09-06)

Primary citation

Statsuk, A.V.,Maly, D.J.,Seeliger, M.A.,Fabian, M.A.,Biggs, W.H.,Lockhart, D.J.,Zarrinkar, P.P.,Kuriyan, J.,Shokat, K.M.
Tuning a three-component reaction for trapping kinase substrate complexes.
J.Am.Chem.Soc., 130:17568-17574, 2008

PubMed Abstract: The upstream protein kinases responsible for thousands of phosphorylation events in the phosphoproteome remain to be discovered. We developed a three-component chemical reaction which converts the transient noncovalent substrate-kinase complex into a covalently cross-linked product by utilizing a dialdehyde-based cross-linker, 1. Unfortunately, the reaction of 1 with a lysine in the kinase active site and an engineered cysteine on the substrate to form an isoindole cross-linked product could not be performed in the presence of competing cellular proteins due to nonspecific side reactions. In order to more selectively target the cross-linker to protein kinases in cell lysates, we replaced the weak, kinase-binding adenosine moiety of 1 with a potent protein kinase inhibitor scaffold. In addition, we replaced the o-phthaldialdehyde moiety in 1 with a less-reactive thiophene-2,3-dicarboxaldehyde moiety. The combination of these two structural modifications provides for cross-linking of a cysteine-containing substrate to its corresponding kinase in the presence of competing cellular proteins.

PubMed: 19053485
DOI: 10.1021/ja807066f

Experimental method

X-RAY DIFFRACTION (2.35 Å)