Infection with the monkeypox virus (MPXV) can result in a clinical condition that is similar to but typically milder than smallpox. As human immunity from smallpox vaccines wanes, monkeypox outbreaks will grow larger and last longer on average. Here, the biological role of the E protein of monkeypox virus, named F13, was investigated using the bioinformatics technique of domain search. Annotation studies revealed that the F13 protein possesses G120, EF-hand, protein kinase (PI3K) and phosphatase (PPM) domains, GB1/RHD3-type GAP/GEF, phospholipase (PhoLip ATPase), and dynamin GTPase domains. Kinase (PI3K) domain is a particular regulator of Dynamin GTPase activity. This result implies that monkeypox virus, like HIV, attaches to cellular receptors and then uses PI3K and GTPase systems to successfully fuse membranes.