Download MendeleyDynamics of loops at the substrate entry channel determine the specificity of iridoid synthases.
Sandholu, A.S., Mohole, M., Duax, W.L., Thulasiram, H.V., Sengupta, D., Kulkarni, K.(2018) FEBS Lett 592: 2624-2635
- PubMed: 29944733
- DOI: https://doi.org/10.1002/1873-3468.13174
- Primary Citation of Related Structures:
5EMH - PubMed Abstract:
Iridoid synthases belong to the family of short-chain dehydrogenase/reductase involved in the biosynthesis of iridoids. Despite having high sequence and structural homology with progesterone 5β-reductase, these enzymes exhibit differential substrate specificities. Previously, two loops, L1 and L2 at substrate-binding pocket, were suggested to be involved in generating substrate specificity. However, the structural basis of specificity determinants was elusive. Here, combining sequence and structural analysis, site-directed mutagenesis, and molecular dynamics simulations, we have shown that iridoid synthase contains two channels for substrate entry whose geometries are altered by L1-L2 dynamics, primarily orchestrated by interactions of residues Glu161 and Gly162 of L1 and Asn358 of L2. A complex interplay of these interactions confer the substrate specificity to the enzyme.
Organizational Affiliation:
Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
