HExxHxxGxxH

HExxHxxGxxH is a protein sequence motif associated with zinc-dependent metalloproteases. It describes a pattern of amino acids in which histidine (H) and glutamate (E) residues, separated by two unspecified residues (x), coordinate a zinc ion at the enzyme’s active site. The extended pattern includes a glycine (G) and an additional histidine (H) further downstream, suggesting a specific arrangement of residues that supports catalysis.

In zinc metalloproteases, the motif contributes to metal binding and catalytic geometry. The first histidine and the glutamate typically participate in coordinating the zinc ion, while the second histidine and the additional histidine later in the pattern can act as ligands or help position water molecules for nucleophilic attack. The glycine residues often provide conformational flexibility in the active-site loop. Together, these residues create the chemical environment necessary for substrate hydrolysis.

Occurrence and significance: The HExxHxxGxxH pattern is found in various protease families across bacteria, archaea, and eukaryotes, as part of larger catalytic domains. It is frequently used in bioinformatics and genome annotation to predict metalloprotease activity from protein sequences. However, the presence of this motif alone does not guarantee proteolytic function; the motif must be considered in the broader protein context, including surrounding residues and overall fold.

Limitations: Motif-based predictions can be confounded by sequence variation and convergent evolution. Experimental validation is essential to confirm metalloprotease activity and zinc coordination for any given protein containing the HExxHxxGxxH pattern.