5IYZ

Tubulin-MMAE complex

5IYZ の概要

• エントリーDOI: 10.2210/pdb5iyz/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002173
• 分子名称: Tubulin alpha-1B chain, N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: cell cycle, cytoskeleton, tubulin fold, microtubule
• 由来する生物種: Rattus norvegicus (Norway Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265902.17

構造登録者

Waight, A.B.,Bargsten, K.,Doronina, S.,Steinmetz, M.O.,Sussman, D.,Prota, A.E. (登録日: 2016-03-24, 公開日: 2016-08-17, 最終更新日: 2024-01-10)

主引用文献

Waight, A.B.,Bargsten, K.,Doronina, S.,Steinmetz, M.O.,Sussman, D.,Prota, A.E.
Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics.
Plos One, 11:e0160890-e0160890, 2016

PubMed Abstract: The auristatin class of microtubule destabilizers are highly potent cytotoxic agents against several cancer cell types when delivered as antibody drug conjugates. Here we describe the high resolution structures of tubulin in complex with both monomethyl auristatin E and F and unambiguously define the trans-configuration of both ligands at the Val-Dil amide bond in their tubulin bound state. Moreover, we illustrate how peptidic vinca-site agents carrying terminal carboxylate residues may exploit an observed extended hydrogen bond network with the M-loop Arg278 to greatly improve the affinity of the corresponding analogs and to maintain the M-loop in an incompatible conformation for productive lateral tubulin-tubulin contacts in microtubules. Our results highlight a potential, previously undescribed molecular mechanism by which peptidic vinca-site agents maintain unparalleled potency as microtubule-destabilizing agents.

PubMed: 27518442
DOI: 10.1371/journal.pone.0160890

実験手法

X-RAY DIFFRACTION (1.8 Å)