HRDmotif

HRDmotif refers to a short, highly conserved amino acid sequence found in the catalytic loop of many protein kinases. The motif comprises histidine-arginine-aspartate (H-R-D) and is a key component of the kinase active site that mediates phosphate transfer from ATP to substrate proteins.

In terms of location, the HRD motif is embedded within the kinase catalytic core, typically in subdomain VIb of the kinase domain. It sits near other conserved features such as the DFG motif of the activation loop and the VAIK motif in the N-terminal lobe. The arrangement of these motifs supports substrate binding, orientation of ATP, and catalysis.

Functionally, the aspartate residue in the HRD motif acts as a catalytic base that facilitates deprotonation of the substrate or activation of water for nucleophilic attack, while the histidine and arginine residues contribute to structural alignment and stabilization of the transition state. Consequences of perturbing this motif range from reduced catalytic efficiency to complete loss of kinase activity, and substitutions are implicated in various diseases, including cancer.

HRD is a highly conserved feature across many serine/threonine and tyrosine kinases, though some pseudo-kinases or divergent kinases may exhibit variations or deviations from the canonical sequence. Because of its conservation and functional importance, the HRD motif is frequently used as a signature in protein kinase annotation, motif searches, and comparative analyses across species.