6c4k

Full length hUGDH with A104L substitution in the absence of ligand

spinqualitylabelsall models 6c4k, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6c4k is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA, PO4 Gene: UGDH (HUMAN) Activity: UDP-glucose 6-dehydrogenase, with EC number 1.1.1.22 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [UGDH_HUMAN] Involved in the biosynthesis of glycosaminoglycans; hyaluronan, chondroitin sulfate, and heparan sulfate. Publication Abstract from PubMed Human UDP-glucose dehydrogenase (hUGDH) oxidizes UDP-glucose to UDP-glucuronic acid, an essential substrate in the phase II metabolism of drugs. The activity of hUGDH is regulated by the conformation of a buried allosteric switch (T131-loop/alpha6 helix). Substrate binding induces the allosteric switch to slowly isomerize from an inactive E* conformation to the active E state, which can be observed as enzyme hysteresis. When the feedback inhibitor UDP-xylose binds, the allosteric switch and surrounding residues in the protein core repack, converting the hexamer into an inactive, horseshoe-shaped complex (E(Omega)). This allosteric transition is facilitated by large cavities and declivities in the protein core that provide the space required to accommodate the alternate packing arrangements. Here, we have used the A104L substitution to fill a cavity in the E state and sterically prevent repacking of the core into the E(Omega) state. Steady state analysis shows that hUGDHA104L binds UDP-xylose with lower affinity and that the inhibition is no longer cooperative. This means that the allosteric transition to the high UDP-xylose affinity E(Omega) state is blocked by the substitution. The crystal structures of hUGDHA104L show that the allosteric switch still adopts the E and E* states, albeit with a more rigid protein core. However, the progress curves of hUGDHA104L do not show hysteresis, which suggests that the E* and E states are now in rapid equilibrium. Our data suggests that hysteresis in native hUGDH originates from the conformational entropy of the E* state protein core. Hysteresis and Allostery in Human UDP-Glucose Dehydrogenase Require a Flexible Protein Core.,Beattie NR, Pioso B, Sidlo AM, Keul ND, Wood ZA Biochemistry. 2018 Nov 20. doi: 10.1021/acs.biochem.8b00497. PMID:30457329 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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