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https://www.learner.org/courses/biology/textbook/proteo/proteo_3.html

Despite advances in techniques for determining protein structure, the structures of many proteins are still unknown...

My question is why? We have many researchers all over the world. We know what our 3 billion DNA is. The governments invest billions of money into medical research. We should have sufficient human resources and technology.

What's stopping us determining structure for all proteins? We need more money? We need more people? We need better technology?

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  • $\begingroup$ How much you already know about determining protein structures? $\endgroup$
    – Arsak
    Apr 4, 2018 at 7:39
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    $\begingroup$ Instead of standing on a soap box making speeches, how about making an effort to find the answer yourself? This is what is expected of people who post to SE Biology. $\endgroup$
    – David
    Apr 4, 2018 at 13:25

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What's stopping us determining structure for all proteins? We need more money? We need more people? We need better technology?

Each unknown structure has a different story. Importantly, not all of the proteins have well-defined structures. But this hasn't historically been appreciated, so lots of effort has been spent structurally resolving regions that are not that ordered. But there are many other explanations for a protein's structure being unknown, most of which fit into two categories.

The putative function can be uninteresting. Most researchers only express and purify proteins that are potentially interesting. There is usually some genetic or pharmacological manipulation that implies a given protein is "interesting." Only the large scale structural genomics projects randomly solve structures, aiming for completion. Even then, these projects have to prioritize proteins that look feasible "on paper."

The protein can resist structure determination Lots of proteins are difficult to express and purify, for a multitude of reasons. For example, the table I just copied from the NorthEast Structural Genomic consortium summarizes their pipeline as follows:

Production stage
targets
cloned          25,924
Expression tested           24,479
Expressed (E > 0)           18,992
Expressed-Soluble (S > 0)           13,946 
Expressed-Soluble (ES >= 9)             11,054 
Fermented           9,440 
Purification attempted          8,691   
Purified (>= 0.5 mg yield)          6,493   
HSQC spectra recorded           2,853   
"Good" HSQC spectra             1,476   
HTP crystal screening           2,845   
Crystal hit             1,480   1,672   
X-Ray structures            608     
NMR structures          496     
Total structures            1,061

So using a combination of X-ray crystallography and solution-state NMR spectroscopy, they solved 1061 structures of 25924 clones, almost all of which were tested for expression. (http://nesg.org/statistics.html)

Crystallography is as automated as it can get right now. Protein NMR and cryoEM have their own niches, and will continue to fill out the gaps. But the science is difficult, and of the well-defined structures, there are still many that haven't been well-described.

(If we could really solve the protein folding problem, we wouldn't need to solve structures at all...)

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    $\begingroup$ Also consider that very often the structure of an individual polypeptide (i.e. single coding gene's product) is meaningless because it only functions as part of a complex, in which its structure is different. $\endgroup$
    – Armatus
    Apr 5, 2018 at 9:56
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The gold standard for determining protein structures is x-ray crystallography. However, in order to perform x-ray crystallography you have to obtain your protein in crystalline form. Many proteins are not soluble in water, so crystallization is difficult or impossible. See this answer for information about the difficulty of crystallizing trans-membrane proteins.

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The answer is most likely priorities. Yes, the process is easier, but it still requires at least some effort and time, which is better spent on other things. As such, grants are unlikely to be given for such trivial work - and this is researchers' job, so if they're not going to be paid for it, they probably won't do it.

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