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The Rossmann fold (or Rossmann-like motif) is one of the most prevalent superfolds in nature, initially identified in a large range of nucleotide-binding proteins that bind diphosphate-containing cofactors such as NAD(H). It comprises a three-layered a/b/a sandwich topology, with two sets of b-a-b-a units forming a single parallel b-sheet (321456 topology) flanked by a-helices [1]. An essential structural feature of the Rossmann fold is a crossover between the second and third b-strands, which forms a pocket adaptable to various ligands.
A minimal Rossmann-like motif is defined as an RLM domain that maintains this doubly-wound three-layer a/b/a sandwich topology and contains the crossover between the second and third strands. It is a key element for the binding of many ligands and small compounds essential for function.
The minimal RLM is the most conserved region within Rossmann-like domains and therefore can be used to identify homologous proteins. The thiamin-diphosphate-binding and TK C-terminal domains in pyruvate ferredoxin oxidoreductase (PFO) are examples of such homologous proteins. The thiamin-diphosphate-binding domain is an RLM with a conserved polar residue that is important for the interaction with ligands, while the TK C-terminal domain has a less conserved surface that is less involved in ligand-binding.
We performed a systematic manual consideration of the RLM in PFO and other homologous multidomain proteins, and found that, despite its conserved RLM core, PFO exhibits considerable structural variation in the a-helices, b-strands and other secondary structure elements. As a result, it was not possible to establish a clear hierarchy of RLM domains. Instead, we revised the largest RLM-containing ECOD X-group ("Other Rossmann-like domains") by creating independent X-groups for most of its H-groups and merging some into other large X-groups such as P-loop domains-like.
This new classification was incorporated into ECOD beginning with version v275 (20200517). Consequently, the pyruvate-ferredoxin oxidoreductase domain III and Lipase_3 families no longer belong to the "Other Rossmann-like domains" X-group. However, the TK C-terminal domains in both PFOR and Lipase_3 remain in the "Other Rossmann-like" X-group.
Similarly, the TK C-terminal domains of several other proteins including human ornithine decarboxylase and pyruvate carboxylase still reside in the "Other Rossmann-like" and PKD/Favodoxin-like X-groups, respectively.
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