7VPS

Crystal structure of the ARM domain of C. glabrata importin alpha

Summary for 7VPS

• Entry DOI: 10.2210/pdb7vps/pdb
• Descriptor: Importin subunit alpha (2 entities in total)
• Functional Keywords: importin, nuclear transport, protein sorting, protein transport
• Biological source: [Candida] glabrata CBS 138 (Yeast, Torulopsis glabrata)
• Total number of polymer chains: 2
• Total formula weight: 98425.69

Authors

Tan, L.,Im, Y.J. (deposition date: 2021-10-17, release date: 2022-09-07, Last modification date: 2023-11-29)

Primary citation

Tan, L.,Chen, L.,Yang, H.,Jin, B.,Kim, G.,Im, Y.J.
Structural basis for activation of fungal sterol receptor Upc2 and azole resistance.
Nat.Chem.Biol., 18:1253-1262, 2022

PubMed Abstract: Fungal transcription factor Upc2 senses ergosterol levels and regulates sterol biosynthesis and uptake. Constitutive activation of Upc2 causes azole resistance in Candida species. We determined the structure of ergosterol-bound Upc2, revealing the ligand specificity and transcriptional regulation. Ergosterol binding involves conformational changes of the ligand-binding domain, creating a shape-complementary hydrophobic pocket. The conserved helix α12 and glycine-rich loop are critical for sterol recognition by forming the pocket wall. The mutations of the glycine-rich loop inhibit ligand binding by steric clashes and constitutively activate Upc2. The translocation of Upc2 is regulated by Hsp90 chaperone in a sterol-dependent manner. Ergosterol-bound Upc2 associates with Hsp90 using the C-terminal tail, which retains the inactive Upc2 in the cytosol. Ergosterol dissociation induces a conformational change of the C-terminal tail, releasing Upc2 from Hsp90 for nuclear transport by importin α. The understanding of the regulatory mechanism provides an antifungal target for the treatment of azole-resistant Candida infections.

PubMed: 36229681
DOI: 10.1038/s41589-022-01117-0

Experimental method

X-RAY DIFFRACTION (2.29 Å)