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Publication Abstract from PubMed

RNase 4, a member of the RNase A superfamily with substrate preference for uridine, has roles in host defence, angiogenesis and neurodegenerative diseases. It also exhibits the highest inter-species amino acid sequence similarity amongst RNase A family members. However, compared to other members of the RNase A family, including EDN, ECP, and ANG, little is known about the molecular basis of substrate specificity in RNase 4. Here we report high to medium resolution structures of native porcine RNase 4 (PL3), a 'substrate-specificity' determining mutant Asp80Ala and their respective complexes with dUMP and dCMP. These structures provide insight into the structural basis of the uridine versus cytosine substrate specificity in RNase 4: in the Asp80Ala mutant (D80A.dCMP), the side chain of Arg101 is positioned further away from the substrate-binding pocket due to the loss of the Asp80 side chain, reducing the repulsion force on the less favoured dCMP from Arg101 and allowing the ligand to occupy the binding pocket. This can also explain the observation that the ligand in the D80A.dCMP complex is stabilised only by a small number of hydrogen bonds. Compared to the previously reported structure of the human RNase 4.dUp complex, the structure of PL3.dUMP complex shows additional hydrogen bonds between the ligand and the protein. In addition, the interaction between Arg101 and the dUMP ligand is absent. These observed differences are likely the result of the flexibility and different 'positioning' of the phosphate group among the mononucleotide ligands. This article is protected by copyright. All rights reserved.

Structural basis of substrate specificity in porcine RNase 4.,Liang S, Acharya KR FEBS J. 2016 Jan 8. doi: 10.1111/febs.13646. PMID:26748441^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.