4RJT

Crystal Structure of Unliganded, Full Length hUGDH at pH 7.0

4RJT の概要

• エントリーDOI: 10.2210/pdb4rjt/pdb
• 関連するPDBエントリー: 2Q3E 2QG4 3PRJ 3PTZ 3TF5 4QEJ
• 分子名称: UDP-glucose 6-dehydrogenase, CHLORIDE ION (3 entities in total)
• 機能のキーワード: oxidoreductase, rossman fold, nucleotide sugar dehydrogenase, nad binding, udp-glucose binding, oxidation, cytosol
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 165423.63

構造登録者

Sidlo, A.M.,Wood, Z.A. (登録日: 2014-10-09, 公開日: 2014-12-31, 最終更新日: 2023-09-20)

主引用文献

Kadirvelraj, R.,Custer, G.S.,Keul, N.D.,Sennett, N.C.,Sidlo, A.M.,Walsh Jr., R.M.,Wood, Z.A.
Hysteresis in Human UDP-Glucose Dehydrogenase Is Due to a Restrained Hexameric Structure That Favors Feedback Inhibition.
Biochemistry, 53:8043-8051, 2014

PubMed Abstract: Human UDP-α-d-glucose-6-dehydrogenase (hUGDH) displays hysteresis because of a slow isomerization from an inactive state (E*) to an active state (E). Here we show that the structure of E* constrains hUGDH in a conformation that favors feedback inhibition at physiological pH. The feedback inhibitor UDP-α-d-xylose (UDP-Xyl) competes with the substrate UDP-α-d-glucose for the active site. Upon binding, UDP-Xyl triggers an allosteric switch that changes the structure and affinity of the intersubunit interface to form a stable but inactive horseshoe-shaped hexamer. Using sedimentation velocity studies and a new crystal structure, we show that E* represents a stable conformational intermediate between the active and feedback-inhibited conformations. Because the allosteric switch occludes the cofactor and substrate binding sites in the inactive hexamer, the intermediate conformation observed in the crystal structure is consistent with the E* transient observed in relaxation studies. Steady-state analysis shows that the E* conformation enhances the affinity of hUGDH for the allosteric inhibitor UDP-Xyl by 8.6-fold (Ki = 810 nM). We present a model in which the constrained quaternary structure permits a small effector molecule to leverage a disproportionately large allosteric response.

PubMed: 25478983
DOI: 10.1021/bi500594x

実験手法

X-RAY DIFFRACTION (2.7 Å)