Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy . Coronaviruses employ between 20 and 30 proteins to carry out their viral replication cycle, including infection, immune evasion, and replication . Among these, nonstructural protein 16 (Nsp16), a 2'-O-methyltransferase, plays an essential role in immune evasion . Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other . Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity . The requirement of this binding partner presents two questions that we investigate in this manuscript . First, how does Nsp10 activate Nsp16? Although experimentally derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved . Therefore, it is unclear how Nsp10 activates Nsp16 . Using over 1 ms of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16's conformational ensemble to activate it . Second, guided by this activation mechanism and Markov state models, we investigate whether Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state . After identifying such a pocket in SARS-CoV2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV1 and MERS but not in human CMTr1 . Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.