I was thinking the exact same thing.   The AC1/AC2 Altair/Ezio era focused on Mediterranean Europe and the Middle East (Italy, Turkey, Israel, Syria), and the AC3/AC4 era so far wants to focus on the Americas (New England, Louisiana, The Caribbean).   So I think a Conquistador-era AC 4.5 would be a natural fit, with maybe a Spaniard (trained by Ezio Auditore, no less, who would be a contemporary of Hernando Cortez) Assassin who defects to the Aztecs and tries to teach them the Craft, and leads an uprising against the Templar Conquistadors.   
 
Tenochtitlan would be an amazing city to explore --- it could easily be the biggest city to ever appear in AC (and easily dwarfed any city in Europe in size and population in the 16th century), and would be absolutely fascinating....lots of color and beauty and majesty, with exotic weaponry and warfare, coupled with horrific images of human sacrifice and true death cults.