Tyrosine-protein kinase c-Src/AMP-PNP complex
Homo sapiens (human)
About a hundred years ago, in 1911, an American doctor working at the Rockefeller University in New York, discovered that some viruses can induce cancer in healthy chicken. The virus that he discovered was named Rous sarcoma virus in his honor, but he had to wait more than 50 years, until 1966, before his discovery was honored with a Nobel prize. Fortunately he lived long enough to see that happen. The Rous sarcoma virus (RSV) is a retrovirus, like HIV, encoding its genetic information in RNA. It is a very simple virus containing genes for only four proteins, two needed for building its envelope and capsid, one, a reverse transcriptase, for turning its RNA into DNA and one more, encoding a tyrosine protein kinase, called Src. It turns out that this kinase is the cancer-causing agent in RSV. Several years later from the discovery of Src gene, a very similar gene of it was found to be present in normal cells, and this gene was named c-Src to distinguish it from viral Src (v-Src). c-Src is harmless by itself, but upon several mutations it can become a cancer-causing gene (oncogene) like v-Src. It is therefore of considerable interest to understand the structure of c-Src as a prototype of an oncogene.
Here we see the structure of this kinase, showing not just its typical kinase domain, but preceding that domain additional sequence that takes part in controlling the activity of Src tyrosine kinase. Instead of adenosine triphosphate (ATP) which is the normal substrate for kinases we see a similar molecule, called AMP-PNP. It is very much like ATP but the connecting oxygen between the second and third phosphate group is replaced by a nitrogen. This compound is not cut by the kinase. At the very end of the Src kinase sequence in a loop that faces the first domain we see a somewhat unusual residue: a tyrosine with a phosphate attached to the hydroxyl group of its sidechain. In cells this tyrosine is phosphorylated by another tyrosine kinase Csk, which results in the inhibition of c-Src activity. Such a phosphorylation of an amino acid sidechain to control the activity of signaling molecules is a frequently used mechanism of nature. The domain of the kinase formed by the beginning of the sequence is divided into two subdomains called SH2 and SH3 domains. The SH2 domain has a binding site for phosphotyrosine and the phosphotyrosine we see here at the end of the kinase domain goes into that binding site.
Protein Data Bank (PDB)
Xu, W. Doshi, A. Lei, M. Eck, M.J. Harrison, S.C.; "Crystal structures of c-Src reveal features of its autoinhibitory mechanism."; Mol.Cell; (1999) 3:629-638 PubMed:10360179.
author: Arno Paehler