RT Journal Article
SR Electronic
T1 Mechanisms by Which Small Molecule Inhibitors Arrest Sec14 Phosphatidylinositol Transfer Protein Activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.01.502361
DO 10.1101/2022.08.01.502361
A1 Xiao-Ru Chen
A1 Lokendra Poudel
A1 Zebin Hong
A1 Philipp Johnen
A1 Sachin S. Katti
A1 Ashutosh Tripathi
A1 Aaron H. Nile
A1 Savana M. Green
A1 Gabriel Schaaf
A1 Fulvia Bono
A1 Vytas A. Bankaitis
A1 Tatyana I. Igumenova
YR 2022
UL http://biorxiv.org/content/early/2022/08/02/2022.08.01.502361.abstract
AB Phosphatidylinositol transfer proteins (PITPs) promote phosphoinositide signaling by enhancing phosphatidylinositol (PtdIns) 4-OH kinase activities in producing signaling pools of PtdIns-4-phosphate. As such, PITPs are key regulators of lipid signaling in eukaryotic cells. While the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activity, the protein and lipid dynamics associated with this critical process are not understood. Herein, we use an integrative structural approach that takes advantage of small molecule inhibitors (SMIs) directed against the major yeast PITP (Sec14) to gain new insights into the mechanics of the Sec14 phospholipid exchange cycle from the perspective of protein, phospholipid and SMI dynamics. Moreover, as Sec14 has emerged as an attractive target for next-generation antifungal drugs, the structures of Sec14 bound to SMIs of four different chemotypes reported in this study provide critical information required for structure-based design of next-generation lead compounds that target Sec14 PITPs of virulent fungi.Competing Interest StatementThe authors have declared no competing interest.