SRC SH2 domain

The Src SH2 domain typifies a large number of those characterized to date. The pTyr fits into a pocket on the opposite side of the central sheet to the pY-r3 pocket (Figure 13.27a). All known SH2 domains bind pTyr in essentially the same way, but some have a different pattern of contacts for the residues that follow. For example, in the Grb2 SH2 domain, a tryptophan side chain from the small sheet fills the pY-r3 pocket, and the bound peptide takes a different course, with important interactions to an asparagine at pY-r2. Screens of peptide libraries have detected the importance of this asparagine. The SH2 domain from PFC-yl contacts five mainly hydrophobic residues that follow pTyr. 

Waksman, G., et al. Binding of a high affinity phosphoty-rosyl peptide to the Src SH2 domain crystal structures of the complexed and peptide-free forms. Cell 72 779-790, 1993. 

The Src homology 2 domain (or SH2-domain) is a protein domain of about 100 amino acid residues first identified in the tyrosine kinase Src. SH2-domain... 

Plummer MS, Holland DR, Shahripour A, Lunney EA, Fergus JH, Marks JS, McConnell P, Mueller WT, Sawyer TK. Design, synthesis, and cocrystal structure of a nonpeptide Src SH2 domain ligand. J Med Chem 1997 40 3719-3725. 

Lunney EA, Para KS, Rubin JR, Humblet C, Fergus JH, Marks JS, Sawyer TK. Structure-based design of a novel series of nonpeptide ligands that bind to the pp60c"src SH2 domain. J Am Chem Soc 1997 119 12471-12476. 

Bibbins KB, Boeuf H, Varmus HE. Binding of the Src SH2 domain to phosphopeptides is determined by residues in both the SH2 domain and the phosphopeptides. Mol Cell Biol 1993 13 7278-7287. 

Metcal CA III, Eyermann CJ, Bohacek RS, Haraldson C, Varkhedkar VM, Lynch B, Bartlett C, Violette S, Sawyer TK. Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydro-phobic binding at the Src SH2 domain. J Comb Chem 2000 2 305-313. 

Studies using free energy calculations for the design and analysis of potential drug candidates are reviewed in section five. The chapters in this section cover drug discovery programs targeting fructose 1,6-bisphosphatase (diabetes), COX-2 (inflammation), SRC SH2 domain (osteoporosis and cancer), HIV reverse transcriptase (AIDS), HIV-1 protease (AIDS), thymidylate synthase (cancer), dihydrofolate reductase (cancer) and adenosine deaminase (immunosuppression, myocardial ischemia). 

A similar terminal-peptide-replacement strategy was used in the Src SH2 domain antagonist program pursued at the Parke-Davis Pharmaceutical Re-... 

Fig. 11. Experimentally determined 3D structure of the Src SH2 domain in complex with compound 48 (ISKJ.pdb [153]). The cyclohexyl moiety binds into the pTyr+3 binding pocket (right)...

Exactly along this line of modification, ARI AD Pharmaceuticals succeeded in generating an Src SH2 domain antagonist containing a bicyclic core element serving as tripeptide mimic, notably AP22161 64 [161]. 

Scheme 11. Development of non-peptide Src SH2 domain antagonists emerging from a computer-aided molecular design strategy... 

Bligh, S.W.A. Haley, T. Lowe, P.N. Measurement of dissociation constants of inhibitors binding to Src SH2 domain protein by non-covalent electrospray ionization mass... 

Peptide scaffold-based design strategies Src SH2 domain antagonists... 

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