The interaction of calcium/calmodulin-dependent protein kinase 11 (CaMKII) with the NR2B subunit of N-methyl-D-aspartate-type glutamate receptor is thought to be one of the important events leading to synaptic plasticity. CaMKII binds NR2B by its catalytic site and by the autophosphorylation site binding pocket (APBP), a non-catalytic site. Mutagenesis of Glu-236, a residue in the APBP of CaMKII that is likely to be interacting with NR2B, influences phosphorylation of NR2B. The phosphorylation of syntide-2, a classical catalytic site substrate of CaMKII, is influenced to a much lesser extent by this mutation. Taken together these results indicate that interaction of NR2B at the non-catalytic site of CaMKII influences catalysis. Our data suggest that kinetic models of peptide substrate phosphorylation by CaMKII should incorporate- the non-catalytic mode of binding of peptides that is dependent on the sequence of the peptide. (C) 2003 Elsevier Inc. All rights reserved.