4zvv

Lactate dehydrogenase A in complex with a trisubstituted piperidine-2,4-dione inhibitor GNE-140Lactate dehydrogenase A in complex with a trisubstituted piperidine-2,4-dione inhibitor GNE-140

Structural highlights 4zvv is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , Gene: LDHA, PIG19 (HUMAN) Activity: L-lactate dehydrogenase, with EC number 1.1.1.27 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [LDHA_HUMAN] Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933]. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue. Publication Abstract from PubMed Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.,Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S, Kwong M, Hong R, Gao M, Del Nagro C, Pusapati R, Ma S, Salphati L, Pang J, Zhou A, Lai T, Li Y, Chen Z, Wei B, Yen I, Sideris S, McCleland M, Firestein R, Corson L, Vanderbilt A, Williams S, Daemen A, Belvin M, Eigenbrot C, Jackson PK, Malek S, Hatzivassiliou G, Sampath D, Evangelista M, O'Brien T Nat Chem Biol. 2016 Aug 1. doi: 10.1038/nchembio.2143. PMID:27479743 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Lactate Dehydrogenase

spinqualitylabelsall models 4zvv, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image