6ROP

KS-MAT DI-DOMAIN OF MOUSE FAS WITH OCTANOYL COA

6ROP の概要

• エントリーDOI: 10.2210/pdb6rop/pdb
• 関連するPDBエントリー: 5MY0 5MY2
• 分子名称: Fatty acid synthase, OCTANOIC ACID (CAPRYLIC ACID), OCTANOYL-COENZYME A (3 entities in total)
• 機能のキーワード: mouse fatty-acid-synthase ks-mat, transferase
• 由来する生物種: Mus musculus (House Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 370355.07

構造登録者

Paithankar, K.S.,Rittner, A.,Grininger, M. (登録日: 2019-05-13, 公開日: 2019-12-04, 最終更新日: 2024-11-13)

主引用文献

Rittner, A.,Paithankar, K.S.,Himmler, A.,Grininger, M.
Type I fatty acid synthase trapped in the octanoyl-bound state.
Protein Sci., 29:589-605, 2020

PubMed Abstract: De novo fatty acid biosynthesis in humans is accomplished by a multidomain protein, the Type I fatty acid synthase (FAS). Although ubiquitously expressed in all tissues, fatty acid synthesis is not essential in normal healthy cells due to sufficient supply with fatty acids by the diet. However, FAS is overexpressed in cancer cells and correlates with tumor malignancy, which makes FAS an attractive selective therapeutic target in tumorigenesis. Herein, we present a crystal structure of the condensing part of murine FAS, highly homologous to human FAS, with octanoyl moieties covalently bound to the transferase (MAT-malonyl-/acetyltransferase) and the condensation (KS-β-ketoacyl synthase) domain. The MAT domain binds the octanoyl moiety in a novel (unique) conformation, which reflects the pronounced conformational dynamics of the substrate-binding site responsible for the MAT substrate promiscuity. In contrast, the KS binding pocket just subtly adapts to the octanoyl moiety upon substrate binding. Besides the rigid domain structure, we found a positive cooperative effect in the substrate binding of the KS domain by a comprehensive enzyme kinetic study. These structural and mechanistic findings contribute significantly to our understanding of the mode of action of FAS and may guide future rational inhibitor designs.

PubMed: 31811668
DOI: 10.1002/pro.3797

実験手法

X-RAY DIFFRACTION (2.7 Å)