I may not be the type of 'pro' you're looking to hear from but...
Getting the mid relationship right is pivotal. Getting guitars to sit in a mix in a useful way is immensely difficult. They are very broadband instruments, and each range needs to be tailored in a useful way. Sometimes you'll get lucky and have all of this from the performer and/or amp tone. Most of the time you won't.
Above all, the ratios of various midrange bands are the most important. 300-600 needs to be controlled to reduce mud, but if overdone will make the guitars sound thin and weak. 600 to 1k needs to be prominent enough so you hear the note, but not so strong as to cloud the ambiance of the mix nor sound 'flat' or 'cardboard'. 1k to 2.5k needs to be controlled so they don't sound too 'pushed', yet if it's overdone, they will sound hollow. 2.5k to 4k needs to be controlled so that they don't get in the way of the vocal. Above this there is all sorts of fizz going around that is source-dependent and needs to be annihilated for the tone to have any chance.
The important thing is to not gauge its 'largeness' when solo'd. I've noticed a trend where many newer guys will overcompensate for poor mid-dispersion in a guitar tone by leaving many lows in it. This is the best way to make your mix suck. Other people with poor perspective will gauge the tone solo'd and say 'wow, that sounds so huge', yet it will sound anything but when put together with other instruments.
When solo'd, a guitar tone should sound relatively thin. This implies that you actually have the bass guitar doing something meaningful within your mix.
The very best and largest mixes almost always have the thinnest and most separated individual elements. It's just the way physics works, it's just the way our hearing works, and it's just the way frequency masking is.
On gain... there is no simple solution. Less isn't always more. More isn't always more. There is however a nice middle ground, a sweet spot that sings well for the material that's being played, and for the amps its being played through. Too little gain will lead to under-powered, hollow mixes, too much will lead to an unintelligible mess.