The fungal pathogen Cryptococcus neoformans is a causative agent of meningoencephalitis in humans. For its pathogenicity, the inositol polyphosphate biosynthetic pathway plays critical roles. Recently, Ipk1 from C. neoformans (CnIpk1) was identified as an inositol 1,3,4,5,6-pentakisphosphate 2-kinase that catalyzes the phosphorylation of IP5 to form IP6, a substrate for subsequent reaction to produce inositol pyrophosphates, such as PP-IP5/IP7. Furthermore, it was shown that deletion of IPK1 significantly reduces the virulence of C. neoformans, indicating that Ipk1 is a major virulence contributor. In this study, we determined a crystal structure of the apo-form of CnIpk1 at 2.35 Å resolution, the first structure for a fungal Ipk1, using a single-wavelength anomalous dispersion method. Even with a low sequence similarity of 26–28%, its overall structure resembles two other Ipk1 orthologs from Arabidopsis thaliana (AtIpk1) and Mus musculus (MmIpk1), and the most crucial residues in the active site are conserved. Unlike AtIpk1 and MmIpk1, however, metal-binding sites for structural stabilization and conformational variations are absent in CnIpk1. The binding environments for substrate IP5 could be inferred by the two different binding sites for sulfate ion in CnIpk1. Taken together, these observations suggest structural similarities and discrepancies for fungal Ipk1 among members of the Ipk1 family and provide structural information for the possible development of drug design for treatment of cryptococcosis.
Bibliographical noteFunding Information:
We thank Dr. Dong-Hoon Yang for his technical assistance. This work was supported by a grant from the Next-Generation BioGreen 21 Program ( Plant Molecular Breeding Center No. PJ01101901 ), Rural Development Administration , Republic of Korea (to S.R.), and also in part by a National Research Foundation of Korea grant ( 2016R1E1A1A01943365 ) from Ministry of Science, ICT and Future Planning , Republic of Korea (to Y-S.B.).
All Science Journal Classification (ASJC) codes
- Structural Biology