Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses.

Viruses often encode proteins that mimic host proteins in order to facilitate infection. Little work has been done to understand the potential mimicry of the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, particularly the receptor-binding motifs, which could be important in determining tropism and druggability of the virus. Peptide and epitope motifs have been detected on coronavirus spike proteins using sequence homology approaches; however, comparing the three-dimensional shape of the protein has been shown as more informative in predicting mimicry than sequence-based comparisons. Here, we use structural bioinformatics software to characterize potential mimicry of the three coronavirus spike protein receptor-binding motifs. We utilize sequence-independent alignment tools to compare structurally known protein models with the receptor-binding motifs and verify potential mimicked interactions with protein docking simulations. Both human and non-human proteins were returned for all three receptor-binding motifs. For example, all three were similar to several proteins containing EGF-like domains: some of which are endogenous to humans, such as thrombomodulin, and others exogenous, such as Plasmodium falciparum MSP-1. Similarity to human proteins may reveal which pathways the spike protein is co-opting, while analogous non-human proteins may indicate shared host interaction partners and overlapping antibody cross-reactivity. These findings can help guide experimental efforts to further understand potential interactions between human and coronavirus proteins.

SARS-CoV-2 3D database: understanding the coronavirus proteome and evaluating possible drug targets.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly growing infectious disease, widely spread with high mortality rates. Since the release of the SARS-CoV-2 genome sequence in March 2020, there has been an international focus on developing target-based drug discovery, which also requires knowledge of the 3D structure of the proteome. Where there are no experimentally solved structures, our group has created 3D models with coverage of 97.5% and characterized them using state-of-the-art computational approaches. Models of protomers and oligomers, together with predictions of substrate and allosteric binding sites, protein-ligand docking, SARS-CoV-2 protein interactions with human proteins, impacts of mutations, and mapped solved experimental structures are freely available for download. These are implemented in SARS CoV-2 3D, a comprehensive and user-friendly database, available at https://sars3d.com/. This provides essential information for drug discovery, both to evaluate targets and design new potential therapeutics.

The current structural glycome landscape and emerging technologies.

Carbohydrates represent one of the building blocks of life, along with nucleic acids, proteins and lipids. Although glycans are involved in a wide range of processes from embryogenesis to protein trafficking and pathogen infection, we are still a long way from deciphering the glycocode. In this review, we aim to present a few of the challenges that researchers working in the area of glycobiology can encounter and what strategies can be utilised to overcome them. Our goal is to paint a comprehensive picture of the current saccharide landscape available in the Protein Data Bank (PDB). We also review recently updated repositories relevant to the topic proposed, the impact of software development on strategies to structurally solve carbohydrate moieties, and state-of-the-art molecular and cellular biology methods that can shed some light on the function and structure of glycans.

ProCarbDB: a database of carbohydrate-binding proteins.

Carbohydrate-binding proteins play crucial roles across all organisms and viruses. The complexity of carbohydrate structures, together with inconsistencies in how their 3D structures are reported, has led to difficulties in characterizing the protein-carbohydrate interfaces. In order to better understand protein-carbohydrate interactions, we have developed an open-access database, ProCarbDB, which, unlike the Protein Data Bank (PDB), clearly distinguishes between the complete carbohydrate ligands and their monomeric units. ProCarbDB is a comprehensive database containing over 5200 3D X-ray crystal structures of protein-carbohydrate complexes. In ProCarbDB, the complete carbohydrate ligands are annotated and all their interactions are displayed. Users can also select any protein residue in the proximity of the ligand to inspect its interactions with the carbohydrate ligand and with other neighbouring protein residues. Where available, additional curated information on the binding affinity of the complex and the effects of mutations on the binding have also been provided in the database. We believe that ProCarbDB will be an invaluable resource for understanding protein-carbohydrate interfaces. The ProCarbDB web server is freely available at http://www.procarbdb.science/procarb.

Mabellini: a genome-wide database for understanding the structural proteome and evaluating prospective antimicrobial targets of the emerging pathogen Mycobacterium abscessus.

Mycobacterium abscessus, a rapid growing, multidrug resistant, nontuberculous mycobacteria, can cause a wide range of opportunistic infections, particularly in immunocompromised individuals. M. abscessus has emerged as a growing threat to patients with cystic fibrosis, where it causes accelerated inflammatory lung damage, is difficult and sometimes impossible to treat and can prevent safe transplantation. There is therefore an urgent unmet need to develop new therapeutic strategies. The elucidation of the M. abscessus genome in 2009 opened a wide range of research possibilities in the field of drug discovery that can be more effectively exploited upon the characterization of the structural proteome. Where there are no experimental structures, we have used the available amino acid sequences to create 3D models of the majority of the remaining proteins that constitute the M. abscessus proteome (3394 proteins and over 13 000 models) using a range of up-to-date computational tools, many developed by our own group. The models are freely available for download in an on-line database, together with quality data and functional annotation. Furthermore, we have developed an intuitive and user-friendly web interface (http://www.mabellinidb.science) that enables easy browsing, querying and retrieval of the proteins of interest. We believe that this resource will be of use in evaluating the prospective targets for design of antimicrobial agents and will serve as a cornerstone to support the development of new molecules to treat M. abscessus infections.

The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.

The midbody is an organelle assembled at the intercellular bridge between the two daughter cells at the end of mitosis. It controls the final separation of the daughter cells and has been involved in cell fate, polarity, tissue organization, and cilium and lumen formation. Here, we report the characterization of the intricate midbody protein-protein interaction network (interactome), which identifies many previously unknown interactions and provides an extremely valuable resource for dissecting the multiple roles of the midbody. Initial analysis of this interactome revealed that PP1ß-MYPT1 phosphatase regulates microtubule dynamics in late cytokinesis and de-phosphorylates the kinesin component MKLP1/KIF23 of the centralspindlin complex. This de-phosphorylation antagonizes Aurora B kinase to modify the functions and interactions of centralspindlin in late cytokinesis. Our findings expand the repertoire of PP1 functions during mitosis and indicate that spatiotemporal changes in the distribution of kinases and counteracting phosphatases finely tune the activity of cytokinesis proteins.