Structural comparison between human and Leishmania infantum Sirtuin 2 NAD-dependent histone deacetylases

Area of Science:

• Structural biology and computational biochemistry
• Parasitology and drug discovery

Background:

• Leishmaniasis is a significant protozoan disease with costly treatments and emerging parasite resistance.
• Sirtuins, specifically Leishmania infantum SIR2-related protein 1 (LiSIR2rp1), are essential targets for anti-parasitic drug development.
• The complete molecular structure of LiSIR2rp1 remains unresolved, hindering drug design.

Purpose of the Study:

• To computationally characterize the full-length LiSIR2rp1, a non-mitochondrial sirtuin.
• To compare the structural patterns of LiSIR2rp1 with its human homolog, SIRT2.
• To provide insights into LiSIR2rp1's behavior for potential therapeutic strategies against leishmaniasis.

Main Methods:

• Generation and validation of molecular models for full-length LiSIR2rp1 using computational tools.
• Molecular dynamics simulations (MDS) to assess protein stability and conformational dynamics.
• Comparative analysis with human sirtuin SIRT2.

Main Results:

• The full-length LiSIR2rp1 model exhibits a highly conserved catalytic core with demonstrated stability via MDS, similar to human sirtuins.
• The central intrinsically disordered region (IDR) of LiSIR2rp1 displayed significant flexibility and overall MDS instability.
• The study identified conformational freedom in the IDR as crucial for LiSIR2rp1 function, mirroring observations in human SIRT2.

Conclusions:

• The computational characterization provides a structural understanding of full-length LiSIR2rp1.
• The findings highlight the importance of the flexible IDR in LiSIR2rp1's function.
• Understanding LiSIR2rp1's structure and dynamics offers a basis for developing novel anti-leishmaniasis therapeutics targeting this enzyme.