I refer to this so often– I need to make a name for it.
A name for how Creationists are always parading about saying protein structures are so perfect and pretty colorful Lego blocks, and they all snap together perfectly, but reality is SO not like that? Reality is a buzzing, floppy, invisible mess?
Invisible is the key word here– Scientists cant look into their microscopes and watch ‘Inner Life of a Cell‘ in real-time.
Figuring out what protein structures ‘look like’ is really damn hard.
Example #1: VSV, Vesicular Stomatitis Virus? It is like, and old-school virus. Old-school. Like, 1920s.
Example #2: We have antiretrovirals that work against the retroviral protein integrase. We have no idea how these drugs work, because we have no idea what integrase looks like. Because we dont know how they work, we dont know how to make them better. We dont know how HIV-1 might evolve resistance, to anticipate changes before they happen.
Were just sorta bumbling around in the dark.
Well, we just cant ‘get’ the structure of HIV-1 integrase. Tried a whole bunch of approaches, and they just dont work. So, researchers tried to figure out the structure of other retroviral integrases in the hopes these other integrases look something like HIV-1s. They found one that worked, yay! We have got ‘a’ structure for ‘a’ integrase! But its not HIV-1 integrase. Popular science journalism has failed completely at noting the importance, the challenges, of using a different virus:
Human foamy viruses (or, prototypic foamy viruses) are a kind of retrovirus, and a kinda retrovirus.
What I mean by that, is that they have the genomic arrangement of a retrovirus (LTRs, gag, pol, env), but they dont behave the same way. Like, HIV-1 is a diploid (+) ssRNA virus. HFV is basically a haploid double-stranded DNA virus– it reverse transcribes most of itself before it buds out, like Hepatitis B.
Furthermore, pol? Its got some mRNA splicing going on– most retroviruses transcribe gag and pol together, and they get chopped up into the appropriate proteins (cupcakes vs sheet cake).
And when Ive compared sequences of HIV-1 integrase and HFV integrase… they dont really look alike. I mean, I just played around on Genebank and lined some sequences up, but they dont look alike to me (correct me if Im wrong!). This doesnt mean a ‘lot’, as viruses are known for having similar structures with apparently no sequence similarity, but Im kinda annoyed at this journalism fail:
99.9% of that article is about HIV-1 integrase. We dont know the 3D structure of HIV-1 integrase. They figured out the 3D structure of HFV integrase, which is only mentioned in passing in that article:
The researchers grew a crystal using a version of integrase borrowed from another retrovirus very similar to its HIV counterpart.
Now, let me be clear, this is really really cool:
Theyve got an integrase structure, and we didnt have that before. Also, integrase inhibitors that work against HIV-1 integrase, work against HFV integrase, so their putative active site structure is right.
The Imperial and Harvard scientists said that having the integrase structure means researchers can begin fully to understand how integrase inhibitor drugs work, how they might be improved, and how to stop HIV developing resistance to them.
is not necessarily true.
Example: We ‘know’ the structure of HIV-1 envelope, Subtype B. Subtype C envelope looks a lot different. We dont have the structure for Subtype C, we just know because ‘variable’ regions of Subtype B can be relatively constant in Subtype C. Different parts of the protein are exposed to the immune system, so they evolve differently. Evolution tells us the structures are different.
So its going to be very hard to infer putative evolutionary pathways from a structure that might be, even slightly, different.
Again, 100% cool research, but time will tell if this structure is great, ‘good enough’, or not really helpful at all for using evolution to improve antiretrovirals.