3prj | pdb_00003prj

Role of Packing Defects in the Evolution of Allostery and Induced Fit in Human UDP-Glucose Dehydrogenase.

spinqualitylabelsall models 3prj, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3prj is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAI, UDX Related: 3ptz 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 Allosteric feedback inhibition is the mechanism by which metabolic end products regulate their own biosynthesis by binding to an upstream enzyme. Despite its importance in controlling metabolism, there are relatively few allosteric mechanisms understood in detail. This is because allostery does not have an identifiable structural motif, making the discovery of new allosteric enzymes a difficult process. The lack of a conserved motif implies that the evolution of each allosteric mechanism is unique. Here we describe an atypical allosteric mechanism in human UDP-alpha-d-glucose 6-dehydrogenase (hUGDH) based on an easily acquired and identifiable structural attribute: packing defects in the protein core. In contrast to classic allostery, the active and allosteric sites in hUGDH are present as a single, bifunctional site. Using two new crystal structures, we show that binding of the feedback inhibitor, UDP-alpha-d-xylose, elicits a distinct induced-fit response; a buried loop translates approximately 4 A along and rotates approximately 180 degrees about the main chain axis, requiring surrounding side chains to repack. This allosteric transition is facilitated by packing defects, which negate the steric conformational restraints normally imposed by the protein core. Sedimentation velocity studies show that this repacking favors the formation of an inactive hexameric complex with unusual symmetry. We present evidence that hUGDH and the unrelated enzyme dCTP deaminase have converged to very similar atypical allosteric mechanisms using the same adaptive strategy, the selection for packing defects. Thus, the selection for packing defects is a robust mechanism for the evolution of allostery and induced fit. Role of Packing Defects in the Evolution of Allostery and Induced Fit in Human UDP-Glucose Dehydrogenase.,Kadirvelraj R, Sennett NC, Polizzi SJ, Weitzel S, Wood ZA Biochemistry. 2011 Jun 3. PMID:21595445 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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