5JPF

Serine/Threonine phosphatase Z1 (Candida albicans) binds to inhibitor microcystin-LR

Summary for 5JPF

• Entry DOI: 10.2210/pdb5jpf/pdb
• Related: 5JPE
• Related PRD ID: PRD_000212
• Descriptor: Serine/threonine-protein phosphatase, Microcystin-LR, MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: yeast-specific serine/threonine phosphatase, microcystin-lr, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Candida albicans (Yeast); More
• Total number of polymer chains: 2
• Total formula weight: 37483.68

Authors

Choy, M.S.,Chen, E.H.,Peti, W.,Page, R. (deposition date: 2016-05-03, release date: 2016-08-31, Last modification date: 2023-11-15)

Primary citation

Chen, E.,Choy, M.S.,Petrenyi, K.,Konya, Z.,Erdodi, F.,Dombradi, V.,Peti, W.,Page, R.
Molecular Insights into the Fungus-Specific Serine/Threonine Protein Phosphatase Z1 in Candida albicans.
Mbio, 7:-, 2016

PubMed Abstract: The opportunistic pathogen Candida is one of the most common causes of nosocomial bloodstream infections. Because candidemia is associated with high mortality rates and because the incidences of multidrug-resistant Candida are increasing, efforts to identify novel targets for the development of potent antifungals are warranted. Here, we describe the structure and function of the first member of a family of protein phosphatases that is specific to fungi, protein phosphatase Z1 (PPZ1) from Candida albicans We show that PPZ1 not only is active but also is as susceptible to inhibition by the cyclic peptide inhibitor microcystin-LR as its most similar human homolog, protein phosphatase 1α (PP1α [GLC7 in the yeast Saccharomyces cerevisiae]). Unexpectedly, we also discovered that, despite its 66% sequence identity to PP1α, the catalytic domain of PPZ1 contains novel structural elements that are not present in PP1α. We then used activity and pulldown assays to show that these structural differences block a large subset of PP1/GLC7 regulatory proteins from effectively binding PPZ1, demonstrating that PPZ1 does not compete with GLC7 for its regulatory proteins. Equally important, these unique structural elements provide new pockets suitable for the development of PPZ1-specific inhibitors. Together, these studies not only reveal why PPZ1 does not negatively impact GLC7 activity in vivo but also demonstrate that the family of fungus-specific phosphatases-especially PPZ1 from C. albicans-are highly suitable targets for the development of novel drugs that specifically target C. albicans without cross-reacting with human phosphatases.

PubMed: 27578752
DOI: 10.1128/mBio.00872-16

Experimental method

X-RAY DIFFRACTION (2.39929733252 Å)