It’s rare to find a paper that connects all of the diverse areas of research of OPIG, but “The rules of disorder or why disorder rules” by Gsponer and Babu (2009) is one such paper. Protein folding, protein-protein interaction networks, protein loops (Schlessinger et al., 2007), and drug discovery all play a part in this story. What’s great about this paper is that it gives numerous examples of proteins and the evidence supporting that they are partially or completely unstructured. These are the so-called intrinsically unstructured proteins or IUPs, although more recently they are also being referred to as intrinsically disordered proteins, or IDPs. Intrinsically disordered regions (IDRs) “are polypeptide segments that do not contain sufficient hydrophobic amino acids to mediate co-operative folding” (Babu, 2016).
Such proteins contradict the classic “lock and key” hypothesis of Fischer, and challenge Continue reading
This week’s issue of Nature has a wonderful “Insight” supplement titled, “The Protein World” (Vol. 537 No. 7620, pp 319-355). It begins with an editorial from Joshua Finkelstein, Alex Eccleston & Sadaf Shadan (Nature, 537: 319, doi:10.1038/537319a), and introduces four reviews, covering:
- the computational de novo design of proteins that spontaneously fold and assemble into desired shapes (“The coming of age of de novo protein design“, by Po-Ssu Huang, Scott E. Boyken & David Baker, Nature, 537: 320–327, doi:10.1038/nature19946). Baker et al. point out that much of protein engineering until now has involved modifying naturally-occurring proteins, but assert, “it should now be possible to design new functional proteins from the ground up to tackle current challenges in biomedicine and nanotechnology”;
- the cellular proteome is a dynamic structural and regulatory network that constantly adapts to the needs of the cell—and through genetic alterations, ranging from chromosome imbalance to oncogene activation, can become imbalanced due to changes in speed, fidelity and capacity of protein biogenesis and degradation systems. Understanding these complex systems can help us to develop better ways to treat diseases such as cancer (“Proteome complexity and the forces that drive proteome imbalance“, by J. Wade Harper & Eric J. Bennett, Nature, 537: 328–338, doi:10.1038/nature19947);
- the new challenger to X-ray crystallography, the workhorse of structural biology: cryo-EM. Cryo-electron microscopy has undergone a renaissance in the last 5 years thanks to new detector technologies, and is starting to give us high-resolution structures and new insights about processes in the cell that are just not possible using other techniques (“Unravelling biological macromolecules with cryo-electron microscopy“, by Rafael Fernandez-Leiro & Sjors H. W. Scheres, Nature, 537: 339–346, doi:10.1038/nature19948); and
- the growing role of mass spectrometry in unveiling the higher-order structures and composition, function, and control of the networks of proteins collectively known as the proteome. High resolution mass spectrometry is helping to illuminate and elucidate complex biological processes and phenotypes, to “catalogue the components of proteomes and their sites of post-translational modification, to identify networks of interacting proteins and to uncover alterations in the proteome that are associated with diseases” (“Mass-spectrometric exploration of proteome structure and function“, by Ruedi Aebersold & Matthias Mann, Nature, 537: 347–355, doi:10.1038/nature19949).
Baker points out that the majority of de novo designed proteins consist of a single, deep minimum energy state, and that we have a long way to go to mimic the subtleties of naturally-occurring proteins: things like allostery, signalling, and even recessed binding pockets for small moleculecules, functional sites, and hydrophobic binding interfaces present their own challenges. Only by increasing our understanding, developing better models and computational tools, will we be able to accomplish this.
Just came across a wonderful PyMOL gallery while creating some images for my (long overdue) confirmation report. A fantastic resource to draw sexy proteins – especially useful for posters, talks and papers (unless you are paying extra for coloured figures!).
It would be great if we had our own OPIG “pymol gallery”.
An example of one of my proteins (1tgm) with aspirin bound to it: