1bhf
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P56LCK SH2 DOMAIN INHIBITOR COMPLEX
OverviewOverview
The crystal structure of human p56(lck) SH2 domain in complex with an, inhibitor containing the singly charged p-(carboxymethyl)phenylalanine, residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been, determined at 1.8 A resolution. The binding mode of the, acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the, pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar, mechanism of SH2 domain inhibition despite its significantly reduced, potency. Observed conformational differences in the side chain of the cmF, residue can be interpreted in terms of maintaining similar interactions, with the SH2 domain as the Tyr(P) residue. The crystal structure of the, free p56(lck) SH2 domain has been determined at 1.9 A resolution and shows, an open conformation for the BC loop and an open phosphotyrosine binding, pocket, in contrast to earlier studies on the src SH2 domain that showed, mostly closed conformation. The structural information presented here, suggests that the carboxymethyl-phenylalanine residue may be a viable, Tyr(P) replacement and represents an attractive starting point for the, design and development of SH2 domain inhibitors with better pharmaceutical, profiles.
DiseaseDisease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this StructureAbout this Structure
1BHF is a Single protein structure of sequence from Homo sapiens with ACE as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
ReferenceReference
Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding., Tong L, Warren TC, Lukas S, Schembri-King J, Betageri R, Proudfoot JR, Jakes S, J Biol Chem. 1998 Aug 7;273(32):20238-42. PMID:9685372
Page seeded by OCA on Mon Nov 12 16:09:42 2007