Rossmann folds are ancient, frequently diverged domains found in many biological reaction pathways where they have adapted for different functions. Consequently, discernment and classification of their homologous relations and function can be complicated. We define a minimal Rossmann-like structure motif (RLM) that corresponds for the common core of known Rossmann domains and use this motif to identify all RLM domains in the Protein Data Bank (PDB), thus finding they constitute about 20% of all known 3D structures. The Evolutionary Classification of protein structure Domains (ECOD) classifies RLM domains in a number of groups that lack evidence for homology (X-groups), which suggests that they could have evolved independently multiple times. Closely related, homologous RLM enzyme families can diverge to bind different ligands using similar binding sites and to catalyze different reactions. Conversely, non-homologous RLM domains can converge to catalyze the same reactions or to bind the same ligand with alternate binding modes. We discuss a special case of such convergent evolution that is relevant to the polypharmacology paradigm, wherein the same drug (methotrexate) binds to multiple non-homologous RLM drug targets with different topologies. Finally, assigning proteins with RLM domain to the Enzyme Commission classification suggest that RLM enzymes function mainly in metabolism (and comprise 38% of reference metabolic pathways) and are overrepresented in extant pathways that represent ancient biosynthetic routes such as nucleotide metabolism, energy metabolism, and metabolism of amino acids. In fact, RLM enzymes take part in five out of eight enzymatic reactions of the Wood-Ljungdahl metabolic pathway thought to be used by the last universal common ancestor (LUCA). The prevalence of RLM domains in this ancient metabolism might explain their wide distribution among enzymes.
Author summaryProtein-ligand interactions are crucial to understanding molecular-level mechanisms of cell functions. A ligand-binding site frequently acts as a protein's functional center, where its structural scaffold orients molecules in the correct conformation for proper function PLOS Computational Biology | https://doi.such as catalysis. These binding or active sites are usually conserved within protein families and can be used to define homologous proteins. However, even homologs may have diverged to functions requiring different active sites. Here we study the structural features and evolution of active sites of proteins containing the Rossmann-like motif (RLM). RLM proteins are numerous in nature and they constitute about 20% of all known 3D structures. Taking into account the prevalence of RLMs in proteins, analysis of their ligands provides general insights into enzyme evolution as well as proposes possible domainbased strategies for drug design in light of polypharmacology. Our analysis shows that RLM enzymes function predominantly in metabolism-these proteins cover 38% of reference metabolic pathways and are involved in numerous me...
The manual classification of protein domains is approaching its 20th anniversary. ECOD is our mixed manual-automatic domain classification. Over time, the types of proteins which require manual curation has changed. Depositions with complex multidomain and multichain arrangements are commonplace. Transmembrane domains are regularly classified. Repeatedly, domains which are initially believed to be novel are found to have homologous links to existing classified domains. Here we present a brief summary of recent manual curation efforts in ECOD generally combined with specific case studies of transmembrane and multidomain proteins wherein manual curation was useful for discovering new homologous relationships. We present a new taxonomy for the classification of ABC transporter transmembrane domains. We examine alternate topologies of the leucine-specific (LS) domain of Leucine tRNA-synthetase. Finally, we elaborate on a distant homologous links between two helical dimerization domains.
Viruses are the most abundant life form and infect practically all organisms. Consequently, these obligate parasites are a major cause of human suffering and economic loss. Rossmann-like fold is the most populated fold among α/β-folds in the Protein Data Bank and proteins containing Rossmann-like fold constitute 22% of all known proteins 3D structures. Thus, analysis of viral proteins containing Rossmann-like domains could provide an understanding of viral biology and evolution as well as could propose possible targets for antiviral therapy. We provide functional and evolutionary analysis of viral proteins containing a Rossmann-like fold found in the evolutionary classification of protein domains (ECOD) database developed in our lab. We identified 81 protein families of bacterial, archeal, and eukaryotic viruses in light of their evolution-based ECOD classification and Pfam taxonomy. We defined their functional significance using enzymatic EC number assignments as well as domain-level family annotations.
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