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J Struct Biol. 2017 Nov;200(2):118-123. doi: 10.1016/j.jsb.2017.09.004. Epub 2017 Sep 15.

Crystal structure of inositol 1,3,4,5,6-pentakisphosphate 2-kinase from Cryptococcus neoformans.

Author information

1
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
2
Department of Biotechnology, Yonsei University, Seoul, Republic of Korea.
3
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea. Electronic address: srheesnu@snu.ac.kr.

Abstract

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 2.35Å 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.

PMID:
28919350
DOI:
10.1016/j.jsb.2017.09.004
[Indexed for MEDLINE]

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