https://orcid.org/0000-0002-5509-1515
Proteins perform incredibly diverse and highly selective functions. It is the consequence of their finely tuned three-dimensional structure. The ‘lock-and-key’ model used for more than a century refers to the classical structure-function paradigm. However, as Professor Giuseppe Zanotti of the University of Padua, Italy reviews for us many protein functions do not require a unique structure. The carriers of such structure-independent functions are the intrinsically disordered regions among ordered domains of proteins (IDRs), or the fully, intrinsically, disordered proteins (IDPs). IDRs and IDPs frequently occur in nature in all proteomes of organisms. The abundance of disorder, the lack of a fixed quaternary protein structure increases proportionally with the complexity of the organism. The presence of significantly disordered regions is estimated around 33% in the eukaryotic proteins and 35% in the human proteome. And in his final note, Giuseppe Zanotti states
I want to point out that the phenomenon of disordered proteins is a characteristic of eukaryotes, whilst is very limited or almost absent in prokaryotes. An indication that it is the complexity of the organisms that requires “disorder”, that at this point should probably be better to rename “flexibility”.
Evidence indicates that the important roles of intrinsic disorder in proteins are associated with a variety of pathophysiologies of diverse diseases such as cancers, diabetes or neurodegenerative disorders. Therefore, there is a strong effort to develop therapeutic drugs that interact with IDRs to modulate protein–protein interactions. Nonetheless, it is difficult to design drugs in the absence of a well-defined conformation of the target.
The prediction of protein tertiary structure from the amino acid sequence has been a challenge for almost seven decades. The energy landscape of a well-folded protein has a well-defined minimum, while it is rather flat in the case of a disordered protein, with several local minima, not separated by significant energy barriers. The biennial Critical Assessment of techniques for protein Structure Prediction (CASP) experiment shows the progress of the field from 1994. AlphaFold in CASP14 was a breakthrough owing to the application of machine learning and multiple sequence alignments. The availability of structure predictions, along with all-important confidence of predictions estimators, on a large scale in AlphaFoldDB (see https://alphafold.com/ developed by Google DeepMind and the European Bioinformatics Institute) provides a novel perspective on IDR prediction.
Giuseppe Zanotti also points out, the distinction between ‘disordered’ and ‘flexible’ is not simply a semantic one, it ranges from a simple flexibility of some limited portions of the polypeptide chain to a fully unfolded, random conformation. His review ‘Intrinsic disorder and flexibility in proteins: a challenge for structural biology and drug design’ summarizes the state of the art of the present knowledge on the subject. He also describes the myriad experimental techniques used to detect disorder. He then addresses how the drug design techniques used for well-folded proteins have been adjusted to the more challenging situation of disorders.
A second review describes ‘Structural biology of SARS-CoV-1/SARS-CoV-2 main protease’ by Andrea Thorn, Yunyun Gao and Johannes Kaub (Institut für Nanostruktur und Festkörperphysik, Universität Hamburg, Germany), Gianluca Santoni (European Synchrotron Radiation Facility, Grenoble, France) and Nicholas Pearce (Department of Chemistry & Pharmaceutical Science, VU University Amsterdam, Netherlands) the overall conformation of the SARS-CoV main protease is considered stable, however, the binding site is highly flexible. The main protease is present in all known coronaviridae. It is a cysteine protease characterized by a conserved cysteine-histidine catalytic dyad. The main protease is the fifth non-structural protein (nsp5). The first SARS-CoV-2 crystal structure was solved within three weeks of the deposition of the viral RNA sequence (25.01.2020) using previously solved main protease structures as homologous models. In the following two years, more than 400 crystal structures of the SARS-CoV-2 main protease have been deposited in the PDB. The main protease is one of the most important non-structural coronavirus proteins, responsible for cutting viral polyproteins into 11 conserved fully functional proteins, which are essential for viral reproduction inside the host cell. Inhibition of the main protease can effectively prevent coronavirus replication, making it an ideal target for drug development.
The new book series SpringerBriefs in Crystallography, under the auspices of the International Union of Crystallography has launched. This is clearly an important idea and initiative of the Series Editor, Professor Massimo Nespolo. The Series ‘aims at presenting highly relevant, concise monographs with an intermediate scope between a topical review and a full monograph’. It, therefore, is different from the IUCr OUP Book Series of Research Monographs and Teaching Books. SpringerBriefs seek to cover a range of content from professional to academic and is to feature compact volumes of 50 to 125 pages. Publications in this Series will help support the Outreach and Education Fund for the IUCr. The first two Brief Books of the Series are reviewed in this issue by Professor John R Helliwell from the Department of Chemistry, University of Manchester, UK. He makes clear that, as Chair of the IUCr OUP Book Series, his two reviews are his personal views.
The first book review is on the ‘Quantum crystallography expectations versus reality’ by Piero Macchi, 2022. The reviewer first offers his own preamble on the history of quantum mechanics and chemistry, which has challenged the greatest of scientists since the outset, including Albert Einstein, before giving opinion on each chapter of the book. He finds the Brief of Piero Macchi fulfils its role being the bridge between the two topics of quantum mechanics and crystallography. He cannot prevent to mention the numerous typos and the high price of the book. The overall outcome is encouraging, the book is thought provoking in its vision and mission. The opinion of the reviewer on the other book of the Series ‘Natural quasicrystals the solar system’s hidden secrets’, by Luca Bindi, 2020, is less confident. The topic is his general interest as it is for most of us, therefore details are given on the first four chapters, the rest which seems to him for specialists, leads him to defer to another review in Acta Crystallographica B by Professor Ron Lifschitz. The aims of these Briefs are interesting and Springer’s aim is to provide them for other branches of science besides crystallography. The aims (https://www.springer.com/series/16236) include ‘A presentation of core concepts that students must understand in order to make independent contributions’. All the crystallographic associations’ teaching commissions we commend need to engage with this initiative of Springer and the IUCr.
As ever we welcome new ideas for review articles and for suggestions regarding books to be reviewed. Please contact me at the e-mail address below. I look forward to welcoming your submissions.