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Bocharov et al. (2013) write that

As there are no structures of full-length RTKs [receptor tyrosine kinases], we do not fully understand how different domains function together to mediate signal transduction inside the cell.

True to the above quote, I've so far only found isolated domains of some RTKs in the PDB, but no complete structures (neither X-ray nor NMR). I am a chemist by training, so am hardly an expert in this area, but it does seem counterintuitive given the general importance of RTKs in cell signalling. Is there a fundamental reason for the lack of RTK structures?

In contrast, there are examples of full-length GPCRs, e.g. rhodopsin (Palczewski et al. 2000). As tsttst brought up in the comments, this seems to be an issue with RTKs being single-pass membrane proteins, whereas GPCRs are multi-pass. How does this affect the ability to obtain a structure?


Bocharov EV, Lesovoy DM, Goncharuk SA, Goncharuk MV, Hristova K, Arseniev AS. 2013. Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies. Structure 21(11):2087–2093. doi: 10.1016/j.str.2013.08.026.

Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, et al. 2000. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480):739–745. doi: 10.1126/science.289.5480.739.

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    $\begingroup$ In the meantime there are some structures, e.g.: Chen et al., J Mol Bio, 2015, or Opatowsky et al., PNAS, 2014 (ncbi.nlm.nih.gov/pmc/articles/PMC4663128, ncbi.nlm.nih.gov/pubmed/24449920) $\endgroup$ – tsttst Oct 18 '18 at 0:12
  • $\begingroup$ Thank you, I don't know why I didn't try Google... Is there still a point in asking why full structures used to be so elusive? $\endgroup$ – orthocresol Oct 18 '18 at 0:16
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    $\begingroup$ One trick is to check the referring papers through google scholar, and one of them highlights the difficulty to crystallize single-pass transmembrane proteins (Valley et al. BBA, 2017, sciencedirect.com/science/article/pii/S0005273617300160#bb0475 ). Asking why single-pass transmembrane sections are difficult to crystallize compared to multi-pass might be a more general and answerable question (the answer would be described in Alberts' text book). $\endgroup$ – tsttst Oct 18 '18 at 4:00
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Large proteins are challenging for NMR: the more amino acids, the more peaks one has to assign. Peak overlap is also more likely the more amino acids you have, making assignment difficult. Some NMR strategies work well for studying dynamics of large proteins, but as far as structure determination is concerned, there definitely is a critical size past which NMR is simply not the tool for the job.

Flexible proteins are challenging for crystallography: too much flexibility can simply prevent crystallization, you can spend years only trying to get crystals, and once you do manage to grow crystals they might diffract poorly or not at all. But crystallography is often very useful to solve high-resolution structures of individual, isolated domains; this is of great help down the road to interpret a lower-resolution cryoEM map of the full-length protein.

Membrane proteins are challenging for biochemistry: purifying them and getting them to remain stable in solution is difficult.

Receptor Tyrosine Kinases (RTKs) are all of that at the same time! Large, flexible membrane proteins.

Now, with tremendous technological progress of cryo-electron microscopy (cryoEM) recently, such challenging structures become more tractable. Conformational flexibility is still an issue, but unlike with crystallography it can be dealt with to some extent (i.e. it won't prevent you from collecting initial data and getting preliminary results that can guide your next attempt).

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  • $\begingroup$ Thank you! With regard to the issue about single-pass vs multi-pass membrane proteins that was brought up in the comments - are the former simply harder to crystallise due to greater inherent flexibility (which seems logical to me)? $\endgroup$ – orthocresol Oct 19 '18 at 0:36
  • $\begingroup$ I am not sure about that, but that could very well be the explanation. GPCRs have flexible loops between transmembrane helices, but these 7 helices are interacting with each other and that probably makes the whole less flexible. $\endgroup$ – Guillaume Oct 19 '18 at 15:07

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