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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2010

AutorInnen: Wojcik, J; Hantschel, O; Grebien, F; Kaupe, I; Bennett, KL; Barkinge, J; Jones, RB; Koide, A; Superti-Furga, G; Koide, S

Titel: A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain.

Quelle: Nat Struct Mol Biol. 2010; 17(4):519-527



Autor/innen der Vetmeduni Vienna:

Grebien Florian

Diese Publikation wurde nicht im Namen der Vetmeduni Vienna erstellt und ist deshalb ausschließlich der persönlichen Publikationsliste des/der Autors/Autorin zugeordnet!


Abstract:
Interactions between Src homology 2 (SH2) domains and phosphotyrosine sites regulate tyrosine kinase signaling networks. Selective perturbation of these interactions is challenging due to the high homology among the 120 human SH2 domains. Using an improved phage-display selection system, we generated a small antibody mimic (or "monobody"), termed HA4, that bound to the Abelson (Abl) kinase SH2 domain with low nanomolar affinity. SH2 protein microarray analysis and MS of intracellular HA4 interactors showed HA4"s specificity, and a crystal structure revealed how this specificity is achieved. HA4 disrupted intramolecular interactions of Abl involving the SH2 domain and potently activated the kinase in vitro. Within cells, HA4 inhibited processive phosphorylation activity of Abl and also inhibited STAT5 activation. This work provides a design guideline for highly specific and potent inhibitors of a protein interaction domain and shows their utility in mechanistic and cellular investigations.

Keywords Pubmed: Amino Acid Sequence
Antibodies, Monoclonal/immunology*
Models, Molecular
Molecular Sequence Data
Oncogene Proteins v-abl/chemistry
Oncogene Proteins v-abl/immunology*
Phosphorylation
Sequence Homology, Amino Acid
src Homology Domains*


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