5ncq

Structure of the (SR) Ca2+-ATPase bound to a Tetrahydrocarbazole and TNP-ATP

spinqualitylabelsall models 5ncq, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ncq is a 1 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: 128, 8T8, K, PCW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AT2A1_RABIT This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Contributes to calcium sequestration involved in muscular excitation/contraction (By similarity). Publication Abstract from PubMed We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate that many tetrahydrocarbazoles also inhibit the mammalian Ca2+-ATPase (SERCA) and Na+,K+-ATPase with an even higher potency than Pma1. We have located the binding site for this compound class by crystallographic structure determination of a SERCA-tetrahydrocarbazole complex to 3.0 A resolution, finding that the compound binds to a region above the ion inlet channel of the ATPase. A homology model of the Candida albicans H+-ATPase based on this crystal structure, indicates that the compounds could bind to the same pocket and identifies pocket extensions that could be exploited for selectivity enhancement. The results of this study will aid further optimization towards selective H+-ATPase inhibitors as a new class of antifungal agents. Tetrahydrocarbazoles are a novel class of potent P-type ATPase inhibitors with antifungal activity.,Bublitz M, Kjellerup L, Cohrt KO, Gordon S, Mortensen AL, Clausen JD, Pallin TD, Hansen JB, Fuglsang AT, Dalby-Brown W, Winther AL PLoS One. 2018 Jan 2;13(1):e0188620. doi: 10.1371/journal.pone.0188620., eCollection 2018. PMID:29293507 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also ATPase 3D structures

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