https://orcid.org/0000-0002-5509-1515
An exceptional event gives a special topicality to this issue of Crystallography Reviews. It has been announced recently that the 2023 Nobel Prize in Physiology or Medicine is awarded by the Nobel Assembly at Karolinska Institutet jointly to Katalin Karikó and Drew Weissman ‘for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19’. It is stated in the explanation, that the laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times. More than 13 billion COVID-19 vaccine doses have been administered globally so far based on different methodologies. The vaccines saved millions of lives and prevented severe disease in many more. The new variants of the virus remain with us, but the mRNA vaccines can easily be adjusted to them. Notwithstanding, societies are open again and have returned to normal conditions and the global economy is recovering.
A vaccine generates active acquired immunity to a particular infectious or malignant disease. Immunization has a long history. Some sources from different parts of the world suggest, that early attempts to prevent the illness of smallpox by intentionally exposing healthy people to the matter collected from a pox sore can be dated to as early as 200 BC. The world’s first successful vaccination was reported by Edward Jenner using cowpox material for inoculation to prevent human smallpox. The first vaccines were based on killed or weakened viruses. Thanks to the progress in molecular biology in recent decades vaccines based on inactivated viral components, rather than whole viruses, have been developed. Viral genetic fragment based vaccines (usually encoding proteins found on the virus surface) are used to make proteins that stimulate the formation of virus-blocking antibodies. The groundbreaking findings for what the Nobel Prize was awarded this year is the understanding of how mRNA interacts with our immune system. This made possible to develop a revolutionary vaccine technology facilitating rapid vaccine production.
Andrea Thorn, the head of a research team at the Institute of Nanostructure and Solid State Physics, University of Hamburg, Germany, contacted Crystallography Reviews at the end of October 2020 with the idea to publish review articles on structural biology of the structurally known proteins from SARS-CoV and SARS-CoV-2. Since the time of the outbreak of the pandemic SARS-CoV-2 related data are being generated and shared, like virus protein structural results and fragment hits. The adopted open science methods (open access, open data and open source) led to research acceleration. The accumulating knowledge on SARS-CoV related structural biology makes possible to improve the understanding of function – structure relations, and it contributes to the development of new vaccines, therapeutics, and medicines.
The RNA genome of SARS-CoV-2 is one of the largest RNA genomes among RNA viruses, encoding for 28 proteins. The structural proteins, which facilitate the transport and host cell infiltration of the viral RNA, are: spike-proteins, envelope-protein, membrane-protein and nucleocapsid protein. Then there are non-structural proteins, essential for the viral life cycle and, finally, accessory proteins, whose function is not completely clarified. During 2022 and 2023 the Thorn’s team in five articles reviewed the structural biology of:
the SARS-CoV-2 endoribonuclease NendoU (nsp15). It acts on single-stranded and double stranded RNA to help SARS-CoV-2 evade detection by the innate immune response. Nsp15 has been proposed as a universal genetic marker to distinguish nidoviruses from all other RNA virus families.
nsp3, the largest protein of SARS-CoV-2, described as the Swiss Army Knife of SARS-CoV-2. Many of its functions still remain a mystery. One of the known functions is that it cleaves the polyprotein, which is translated first upon infection.
the SARS-CoV-2 nucleocapsid. The primary role of the nucleocapsid is to protect the viral RNA by packaging it in a ribonucleoprotein complex inside the virion.
the SARS-CoV-2 accessory proteins. The accessory proteins primarily serve to block host cell reactions to viral infection.
the SARS-CoV/SARS-CoV-2 main protease (nsp5). It is a cysteine protease characterized by a conserved cysteine-histidine catalytic dyad. The main protease is responsible for cutting viral polyproteins into eleven conserved fully functional proteins, which are essential for viral reproduction.
This third issue of Volume 29 of Crystallography Reviews reports two further reviews, one on the structural biology of non-structural proteins (nsp14, nsp16 and nsp10) of SARS-CoV-2, as well as one on the envelope and membrane-proteins of SARS-CoV-2, handled by the topic editor Michele Cianci.
Cameron Fyfe, Lea von Soosten, Andrea Thorn (Institut für Nanostruktur und Festkörperphysik, Universität Hamburg, Germany) and Gianluca Santoni (European Synchrotron Radiation Facility, Grenoble, France) report the ‘Structural Biology of SARS-CoV-2 Exoribonuclease/N7 Methyltransferase (nsp14), 2′ O methyltransferase (nsp16), and their enhancing protein (nsp10)’. The full-length versions of the isolated non-structural nsp10, and its two heterodimeric complexes nsp10–nsp14 and nsp10–nsp16 are available from both crystallographic and cryo-EM experiments. Various structures have been obtained of nsp10–nsp14 in complex with RNA as well as part of the replication–transcription complex (RTC). The currently available structures give high-resolution information of substrate and ligand binding that will be useful in future drug design. There are various possibilities for active sites which could be targeted with therapeutics. This review provides an overview of the role and structure of these non-structural proteins.
The ‘SARS-CoV-2 Envelope Protein and its relationship to the Membrane Protein’ is presented by Andrea Thorn and her group, Luise Kandler, Oliver Kippes, Maximilian Edich, Sabrina Stäb (all from the Institut für Nanostruktur und Festkörperphysik, Universität Hamburg, Hamburg, Germany), and Gianluca Santoni (European Synchrotron Radiation Facility, Grenoble, France). The small-sized envelope-protein plays multiple roles upon infection, leading to the severe symptoms observed in Covid-19 patients. E-protein limits stress responses in infected cells, thereby ensuring extended cell lifetimes and it is involved in expressing additional entry factors, thereby accelerating the infection process within the host organism. The E- and M-proteins are essential for the viral infection cycle, especially during virion assembly, where they interact to form virion particles. The article gives structural overviews, a description of protein-protein interactions, and discusses therapeutic interests.
Anharmonism of thermal vibrations of atoms is a fundamental issue, which underpins various properties, e.g. thermal expansion or thermal conductivity. The rapid development of both X-ray and neutron diffraction techniques, high-temperature studies, possibilities of (semi-)analytical absorption description, they all had drastically improved the data quality and it permitted to perform anharmonic refinements. The ‘anharmonic’ approaches are now widely used for the description of thermal vibrations and displacements of the atoms in solid phase. The article on ‘Gram–Charlier approach for anharmonic atomic displacements in inorganic solids: a review’ by S. N. Volkov (Kola Science Centre, Russian Academy of Sciences and Grebenshchikov Institute of Silicate Chemistry), D. O. Charkin (Kola Science Centre and Lomonosov Moscow State University), S. M. Aksenov (Kola Science Centre), V. A. Firsova, and R. S. Bubnova (Grebenshchikov Institute of Silicate Chemistry) from Russia provides a valuable overview of the issue. The authors clearly show the reasons why in principle of using a harmonic approximation cannot be sufficient in many cases. They present how to get arguments about the need to introduce an anharmonic description and demonstrate the use of difference Fourier maps at different stages of the introduction of individual anharmonic terms. All published structures, in which the anharmonic model was applied, are summarized. The references are collected which report anharmonic refinement sorted by the type of elements. Finally, the last chapter presents the new software ‘Anharmonicity’ developed by the authors, which interprets the results of anharmonic refinement.
The book review of this issue of Crystallography Reviews is on Joel Bernstein’s ‘Polymorphism in Molecular Crystals’, 2nd Edition, Oxford University Press, New York, 2020 written by Nikoletta B. Báthori from the Cape Peninsula University of Technology, Cape Town, South Africa. This is the second edition of the legendary book, which can be considered as the testament to Bernstein's legacy in the field of solid-state chemistry. The author recalls her personal memories, how enthusiastic Joel Bernstein was about the possibility of writing an updated version of the first edition. As the reviewer writes, the objective of the first edition was straightforward: ‘to summarize the knowledge of polymorphism in molecular crystals in a single reference that serves as a starting point for anyone from novices to experts in solid state chemistry’. The second edition was published posthumous. The solid-state community received a book, which is extended by more than 200 pages and a thousand of references. Most of the chapters are updated with the most important recent developments, and some chapters are extended significantly (exploring the crystal form landscape, computational aspects of polymorphism, polymorphism of pharmaceuticals). More details can be found in the book review, along with some gems revealed in the book, and also some critics conceived from the point of view of the reviewer. The final conclusion is that the nature of the discussions makes the book ‘an excellent catalyst for future research’.
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.