36wk

Mevalonate kinase from Saccharomyces cerevisiae with dimethylallyl pyrophosphate (DMAPP) bound

spinqualitylabelsall models 36wk, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 36wk is a 1 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.93Å Ligands: DMA, EDO, MG, TAR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ERG12_YEAST Mevalonate kinase; part of the second module of ergosterol biosynthesis pathway that includes the middle steps of the pathway (PubMed:1645230). ERG12 converts mevalonate into 5-phosphomevalonate (PubMed:1645230). The second module is carried out in the vacuole and involves the formation of farnesyl diphosphate, which is also an important intermediate in the biosynthesis of ubiquinone, dolichol, heme and prenylated proteins. Activity by the mevalonate kinase ERG12 first converts mevalonate into 5-phosphomevalonate. 5-phosphomevalonate is then further converted to 5-diphosphomevalonate by the phosphomevalonate kinase ERG8. The diphosphomevalonate decarboxylase MVD1/ERG19 then produces isopentenyl diphosphate. The isopentenyl-diphosphate delta-isomerase IDI1 then catalyzes the 1,3-allylic rearrangement of the homoallylic substrate isopentenyl (IPP) to its highly electrophilic allylic isomer, dimethylallyl diphosphate (DMAPP). Finally the farnesyl diphosphate synthase ERG20 catalyzes the sequential condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate (PubMed:32679672). Publication Abstract from PubMed The mevalonate pathway diverts acetyl-CoA from central metabolism to produce isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), the universal precursors to all steroids and isoprenoids in biology. Mevalonate kinase (MK) catalyzes a key regulatory step of mevalonate pathway in many eukaryotes, in which several downstream isoprenoid pyrophosphates act as feedback inhibitors. Known MK inhibitors vary widely in size, including IPP and DMAPP (five carbons, C(5)), geranyl pyrophosphate (GPP, C(10)), farnesyl pyrophosphate (FPP, C(15)), and geranylgeranyl pyrophosphate (GGPP, C(20)). These inhibitors compete for binding at a single site, yet how the enzyme is able to accommodate inhibitors of such varying sizes remains unknown. In this work, we first characterized the inhibition kinetics of all five of these inhibitors using MK from Saccharomyces cerevisiae (ScMK), revealing an inhibition potency that ranges approximately two orders of magnitude. We then solved X-ray crystal structures of ScMK bound to all five inhibitors as well as the structure of apo ScMK to shed light on how inhibitors of such varying sizes may all bind to the same site. In all, this suite of inhibitor-bound MK structures provides the first comprehensive structural depiction of MK feedback inhibition, a key regulatory mechanism of the mevalonate pathway of steroid and isoprenoid precursor biosynthesis. Structural basis of mevalonate pathway regulation by feedback inhibition of mevalonate kinase.,D'Emilia RLS, McCaskey KA, Ragwan ER, Kim JH, Chang V, Tang MM, Kung Y J Biol Chem. 2026 Sep 17:113566. doi: 10.1016/j.jbc.2026.113566. PMID:42754161 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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