Prague is the setting for Deus Ex's fourth adventure: Deus Ex: Mankind Divided, set in 2029.
It's a beautiful city, and the game imagines an elegant and at times brutalist future for it, blending the old town with new structures and ideas. Glass, metal, concrete, and police in mech-suits crawl over the old gothic buildings, in a style the artists dubbed "techno-feudalism". This post is just a lighthearted comparison between the game and real life, seeing how they match up and if there are any interesting nods to the real city hidden within the game. At the end I've linked an interview with some of the game's designers that gives some insight into how they built the city.
Past
Prague has evolved and radiated out from the seat of power: Pražský hrad, on the hill west of the river. The city boomed due to it's central position in Europe, situated on a river for trade, and with defensible terrain. In the 14th century Prague became the seat of the Holy Roman Empire, during which the city prospered and grew, it's this period which created many of the elaborate gothic landmarks Prague is famous for today.
In this picture from 1607, much of the distincitive skyline remains visible today
2029
The slices of prague seen in Deus Ex are only a small fraction of the city. Specifically, the map is within Staré Město: the old town on the east side of the riverOther maps in the game, as well as the in-game compass, change the orientation to make west north and east become south . Some maps in-game are nice enough to overlay the map on a real map, placing the map just between Mánes Bridge and Charles Bridge. Convinient, as that's where all the landmarks are. As we can see, the street layouts don't match, and the game world isn't an attempt to accurately model the real Prague. The central train line that bisects the map doesn't exist in real life, but otherwise the game map is somewhat true to this placement, with the in-game architecture roughly correct for this area of the city, and it makes sense for the landmarks in the game such as Palisade Bank to be situated in this central part of the city.
A map found within a disused tourist office in-game
Here are the real streets that area relates to, courtesy of Google earth:
The buildings are pretty much as they are now, and as they existed in the 20th century, but with some extra sculptures.
There's now a metro though, and some ridiculously large, impossibly cantilevered futuristic structures loom overhead.
The spires on the hill are a fairly accurate rendition of Pražský hrad. The silhouette is the same as the old drawing further up, although flipped
Rooftops and the mysterious case of the towers
The town, especially the old town, is quite dense in the medieval European style, and as you play an elite cyborg ninja sniper with a recently discovered knack for teleportation, there's quite a few opportunities to admire the skybox and look out over the roofs of Prague. In fact this is one of the main ways you get a sense of the city's geography while playing, as otherwise you're walking through narrow alleys, tunnels, and vents.
One of Prague's distinguishing features are the gothic spires attached to the bridges, clock towers, and old town hall, so much that is has been known as the city of 100 spires:
A nice touch in Mankind Divided is that you can occasionally glimpse these poking out of the skyline.
When I noticed this I tried to cross reference them, to see if the approximate in game positions made sense. I came to the conclusion they didn't match up, as in the game you can find more towers than there are in real life, and the relative directions don't quite make sense:
The Clocktower
One of the mentioned towers is Prague's astronomical clocktower, located in the old town by the open square and town hall. You can in fact find the clocktower in the game, recognisable by it's distinctive shape. In 2029, the bottom of the tower is clad in brutalist concrete sculpture, obscuring the famous clock at its base. You can find a clip of the in-game clocktower during the daytime here, showing off the concrete structure: https://youtu.be/eMFL7ettk7Y?t=42.
Prague Astronomical Clock. The lower part was painted by Joseph Mánes, who gives his name to one of the bridges discussed earlier
Bridges and castles
Prague is famous for it's bridges, especially Charles Bridge, which look beautiful at night, and criss-cross the Vltava. Sadly due to the small map, there isn't an opportunity to walk across one, but there are a couple of neat viewpoints. In real life, looking west across the river from old town shows a view of Prasky Hrad. But in the game they've flipped the view, confusingly if you look west, the view you see is that of the east side. This is shown in the 2 images below, with the same distinctive rooftops highlighted in each:
Across the Vltava in the game, remembering the game's map places us on the east side of the river
The same view in reality
The real view west from the game's position on the east would show the castle on the hill to the north west:
The Theatre
The exterior of the "Dvali" theatre, the setting of the "Hunting Down the Final Clues" mission, shows off a domed building on a corner, with a canopy and tympanum 
For more 'What style is this building and what do I call this funny bit' information, check out Rice's Architectural Primer. It's a little hard to make out in the image below, due to the large mech and pouring rain. R.U.R on the billboard is a reference to Rossum's Universal Robots, a Czech play which first brought about the term "robot", and discussed the ideas about the rights of androids, a central theme of the recent Deus Ex entries.
Exterior of un-named theatre in Deus Ex: Mankind Divided
This actually appears to be a scaled down model of the Art Nouveau Prague Municipal House, not really a theatre. You can see the same corner shape, the distinctive dome, narrow arched windows, as well as the canopy and tympanum.
Exterior of Prague municipal house in real life, inspiration for the in-game theatre
The Time Machine
"The Time Machine" is a bookshop encountered early during the Deus Ex story, with no single inspiration I could find. The closest reference I could find was that the quirky book-arched front door is reminisicent of the window of This shop, shown below. Prague's famous library, Strahov Monastery Library doesn't seem to be referenced, and is geographically outside of the game's area, situated west of the river close to the castle.
The naming of The Time Machine is another neat nod to the game's themes and classic science fiction. HG Well's "The Time Machine" is a seminal sci-fi work, also looking forward and envisioning a more divided future, with vast inequality between rich and poor, in which the working classes have lost their humanity.
There the parallels end, since H.G Wells' novel ends with the protagonist travelling forwards in time to when the world is filled with giant crabs and the sun becomes a red giant, and in the game you fly to London to fight the Illuminati, both equally plausible and compelling visions.Another link to classic sci-fi can be found nearby: a Jewellers called "Vern's Jewels" 
Wrapping up
I hope that's been an interesting dive into the city, with a bit of architecture and sci-fi history sprinkled in. If you've not played it I can heartily recommend playing the game, and if you want to read more, the following links provide some insights from the game's level designers: