Abstract
Human genome contains a group of more than a dozen similar genes with diverse biological functions including antiviral, antibacterial and angiogenesis activities. The characterized gene products of this group show significant sequence similarity and a common structural fold associated with binding and cleavage of ribonucleic acid (RNA) substrates. Therefore, these proteins have been categorized as members of human pancreatic-type ribonucleases (hRNases). hRNases differ in cell/tissue localization and display distinct substrate binding preferences and a wide range of ribonucleolytic catalytic efficiencies. Limited information is available about structural and dynamical properties that influence this diversity among these homologous RNases. Here, we use computer simulations to characterize substrate interactions, electrostatics and dynamical properties of hRNases 1–7 associated with binding to two nucleotide substrates (ACAC and AUAU). Results indicate that even with complete conservation of active-site catalytic triad associated with ribonucleolytic activity, these enzymes show significant differences in substrate interactions. Detailed characterization suggests that in addition to binding site electrostatic and van der Waals interactions, dynamics of distal regions may also play a role in binding. Another key insight is that a small difference in temperature of 300 K (used in experimental studies) and 310 K (physiological temperature) shows significant changes in enzyme-substrate interactions.
Highlights
A set of related human genes encoding for enzymes that cleave ribonucleic acid (RNA) substrates exhibit diverse biological functions such as angiogenesis, antiviral, antibacterial, and/or cytotoxic activities
Seven human ribonuclease substrate complexes were prepared based on X-ray/nuclear magnetic resonance (NMR) structures with the following PDB codes: 2K11 [31], 1GQV [32], 1QMT [33], 1RNF [34], 1ANG [35], 2HKY [36] and 7RSA [37], while hRNase6 was crystallized in our group [38]
The starting coordinates for the substrate phosphate and ribose sugar backbone were adopted from a bovine ribonuclease A (bRNaseA)-substrate complex published previously (PDB code 1RCN), and the nucleotide bases were added computationally
Summary
A set of related human genes encoding for enzymes that cleave ribonucleic acid (RNA) substrates exhibit diverse biological functions such as angiogenesis, antiviral, antibacterial, and/or cytotoxic activities. Eight of the encoded enzymes (canonical members) show conservation of two active-site histidine residues and a lysine associated with the catalytic mechanism of ribonucleolytic cleavage. An additional five catalytically inactive (non-canonical members) pseudogenes were identified in the human genome [1,2,3,4]. Nucleotide substrate binding in human ribonucleases designed the study with inputs from SCC and ND.
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