PDBsum entry 4jdi

Transferase/peptide

PDB id: 4jdi

Contents

Protein chain

290 a.a.

Ligands

ARG-ARG-ARG-ARG-SER-TRP

ANP

Metals

_MG ×2

Waters ×139

References listed in PDB file

Key reference

• Title: Identification of a major determinant for serine-Threonine kinase phosphoacceptor specificity.
• Authors: C.Chen, B.H.Ha, A.F.Thévenin, H.J.Lou, R.Zhang, K.Y.Yip, J.R.Peterson, M.Gerstein, P.M.Kim, P.Filippakopoulos, S.Knapp, T.J.Boggon, B.E.Turk.
• Ref.: Mol Cell, 2014, 53, 140-147. [DOI no: 10.1016/j.molcel.2013.11.013]
• PubMed id: 24374310

Abstract

Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many serine-threonine kinases display a significant preference for serine or threonine as the phosphoacceptor residue. Here we show that a residue located in the kinase activation segment, which we term the "DFG+1" residue, acts as a major determinant for serine-threonine phosphorylation site specificity. Mutation of this residue was sufficient to switch the phosphorylation site preference for multiple kinases, including the serine-specific kinase PAK4 and the threonine-specific kinase MST4. Kinetic analysis of peptide substrate phosphorylation and crystal structures of PAK4-peptide complexes suggested that phosphoacceptor residue preference is not mediated by stronger binding of the favored substrate. Rather, favored kinase-phosphoacceptor combinations likely promote a conformation optimal for catalysis. Understanding the rules governing kinase phosphoacceptor preference allows kinases to be classified as serine or threonine specific based on their sequence.