Apparently a temporary thing but there are currently no direct buses between Panajachel and Guatemala City. Knowing this is important but there are some decent bus alternatives. Let me explain them.
The first thing you need to know is that Los Encuentros, a little nothing town on the Pan American Highway is really transportation central. At any one time there is usually around ten buses there heading for somewhere. It is generally not a place where you wait for a bus — just where you get off one and on another.
From Pana there are regular buses to Los Encuentros. They leave from the same place as the buses to Sololá (almost in front of Tropigas) and cost Q5 for the trip. An alternative is to take the bus to Sololá (Q3) walk about 30 meters and catch a bus from there to Los Encuentros (Q2.5). Either way, it’s an easy trip. Note that you have additional choices. For example, the bus from Pana to Xela goes to Los Encuentros before heading back west on the Pan Am.
The bus parking lot is on the north side of the Pan Am. You will need to cross the highway to catch an eastbound bus. Many times there will be ayudantes from the eastbound buses waiting for people arriving from other buses so don’t be surprised if someone whisks you off to a waiting bus. Note that there is a big MarcoPolo bus from Xela on its way to Guatemala City that passes through Los Encuentros at about 1030. It costs Q25 instead of the more typical Q20 but it is roomy and comfortable.
In Guatemala City all the buses heading West wait along Calle 41 and then pick up passengers along Calzada Roosevelt. While this may sound like a complicated unknown, it isn’t and they are looking for customers so you are unlikely to get missed. Note that if you are near a Transmetro station, head to the Santa Cecelia one (one station north of Trebol). Get off and cross over the highway lanes heading into the center of town. (If you were on an outbound bus, this would be to your left. At the bottom of the stairs, just continue along the sidewalk. In a block you meet a natural curve to the left and you are now on Calle 41. It is about two more blocks until you encounter the waiting buses.
The most complicated part of this whole adventure is picking the right bus. It is not going to say Panajachel and, generally, not even Los Encuentros. The question you want to ask is if it goes to/through Los Encuentros. A couple of examples of buses that do are once going to Quiche and Xela.
The fare to Los Encuentros will be Q20. Once there there is virtually always a bus waiting for Sololá and sometimes for Pana.
As complicated as all this sounds, the reality is that you need little in the way of Spanish skills to pull it off and at least for me, it is generally fun. It is also always faster than the shuttles that stop in Antigua.