5G1P

Aspartate transcarbamoylase domain of human CAD bound to carbamoyl phosphate

5G1P の概要

• エントリーDOI: 10.2210/pdb5g1p/pdb
• 関連するPDBエントリー: 5G1N 5G1O
• 分子名称: CAD PROTEIN, PHOSPHORIC ACID MONO(FORMAMIDE)ESTER (3 entities in total)
• 機能のキーワード: transferase, de novo pyrimidine synthesis, transcarbamoylase, transcarbamylase, cad, carbamoyl phosphate synthetase, dihydroorotase, cooperativity
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm : P27708
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 210314.65

構造登録者

Ruiz-Ramos, A.,Grande-Garcia, A.,Moreno-Morcillo, M.D.,Ramon-Maiques, S. (登録日: 2016-03-29, 公開日: 2016-06-22, 最終更新日: 2024-01-10)

主引用文献

Ruiz-Ramos, A.,Velazquez-Campoy, A.,Grande-Garcia, A.,Moreno-Morcillo, M.,Ramon-Maiques, S.
Structure and Functional Characterization of Human Aspartate Transcarbamoylase, the Target of the Anti-Tumoral Drug Pala.
Structure, 24:1081-, 2016

PubMed Abstract: CAD, the multienzymatic protein that initiates and controls de novo synthesis of pyrimidines in animals, associates through its aspartate transcarbamoylase (ATCase) domain into particles of 1.5 MDa. Despite numerous structures of prokaryotic ATCases, we lack structural information on the ATCase domain of CAD. Here, we report the structure and functional characterization of human ATCase, confirming the overall similarity with bacterial homologs. Unexpectedly, human ATCase exhibits cooperativity effects that reduce the affinity for the anti-tumoral drug PALA. Combining structural, mutagenic, and biochemical analysis, we identified key elements for the necessary regulation and transmission of conformational changes leading to cooperativity between subunits. Mutation of one of these elements, R2024, was recently found to cause the first non-lethal CAD deficit. We reproduced this mutation in human ATCase and measured its effect, demonstrating that this arginine is part of a molecular switch that regulates the equilibrium between low- and high-affinity states for the ligands.

PubMed: 27265852
DOI: 10.1016/J.STR.2016.05.001

実験手法

X-RAY DIFFRACTION (3.19 Å)