There have been such advances in crystallography in the past couple decades. Molecules that were thought too difficult to crstalize have been. Membrane proteins, including a number of GPCR and the ribosome.
These feats have been awarded Nobel prizes.
Yet, I feel in the ribosome case, one of the pioneers in ribosome structure and function wasn’t awarded the prize as they gave it to three crystallographers for, to my mind, essentially confirming the structure he’d determined by other means.
I am aware of the advances being made to crystallize membrane proteins, as that particular field was advancing when I was in graduate school in the late 1990s.
The problem with the protein I worked with was that it is incredibly unstable. I used to synthesize it in vitro with 35S labeling; even if I ran a gel immediately after synthesis, the lane was a mess of degradation products. I never quantitated how much was lost to degradation, but I can estimate that less than a quarter—probably less than 10%—of the protein was intact.
That instability makes crystallography impossible.
We were collaborating with a crystallographer to try to crystallize smaller fragments of the protein, for instance, just the basic helix-loop-helix domain—but we just couldn’t synthesize it in quantities sufficient for crystal studies. So when someone published a crystal structure of a related basic helix-loop-helix protein, we were ecstatic.