5VXA

Structure of the human Mesh1-NADPH complex

Summary for 5VXA

• Entry DOI: 10.2210/pdb5vxa/pdb
• Descriptor: Guanosine-3',5'-bis(diphosphate) 3'-pyrophosphohydrolase MESH1, ZINC ION, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (8 entities in total)
• Functional Keywords: mesh1 nadph, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 43137.83

Authors

Rose, J.,Zhou, P. (deposition date: 2017-05-23, release date: 2018-05-23, Last modification date: 2022-03-30)

Primary citation

Ding, C.C.,Rose, J.,Sun, T.,Wu, J.,Chen, P.H.,Lin, C.C.,Yang, W.H.,Chen, K.Y.,Lee, H.,Xu, E.,Tian, S.,Akinwuntan, J.,Zhao, J.,Guan, Z.,Zhou, P.,Chi, J.T.
MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.
Nat Metab, 2:270-277, 2020

PubMed Abstract: Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosis-inducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.

PubMed: 32462112
DOI: 10.1038/s42255-020-0181-1

Experimental method

X-RAY DIFFRACTION (2.1 Å)