Abstract:
:The pH dependence of the affinity of a 11-mer phosphotyrosine (pY) peptide (EPQpYEEIPIYL-NH2) for the SH2 domain of the tyrosine kinase p56(lck) was investigated with surface plasmon resonance (SPR). From SPR competition experiments the affinity in solution was obtained. The pH dependence of the affinity in solution can be well described by a proton linkage model with a single pK(a) shift upon binding, from 6.1 to 4.7. This shift is ascribed to the transition from the -2 to the -1 ionisation state of the tyrosine phosphate group. Based on the X-ray structure for the complex with Lck SH2, a pK(a) value of 5.3 for the bound pY peptide was computed, modelling the solvated protein as a system of point charges in a continuum. With the phosphate in the -2 state the binding energy is 1.8 kcal/mol more favourable than for the -1 state, corresponding to a 20-fold higher affinity. A proper charge is relevant in the design of potential therapeutic Lck SH2 ligands with mimics for the metabolically unstable tyrosine phosphate group.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
de Mol NJ,Gillies MB,Fischer MJdoi
10.1016/s0968-0896(01)00407-2subject
Has Abstractpub_date
2002-05-01 00:00:00pages
1477-82issue
5eissn
0968-0896issn
1464-3391pii
S0968089601004072journal_volume
10pub_type
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