2NZT

Crystal structure of human hexokinase II

2NZT の概要

• エントリーDOI: 10.2210/pdb2nzt/pdb
• 分子名称: Hexokinase-2, alpha-D-glucopyranose, 6-O-phosphono-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: glucose, glucose-6-phosphate, non-protein kinase, hexokinase, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 202990.75

構造登録者

Rabeh, W.M.,Zhu, H.,Nedyalkova, L.,Tempel, W.,Wasney, G.,Landry, R.,Vedadi, M.,Arrowsmith, C.H.,Edwards, A.M.,Sundstrom, M.,Weigelt, J.,Bochkarev, A.,Park, H.,Structural Genomics Consortium (SGC) (登録日: 2006-11-25, 公開日: 2006-12-05, 最終更新日: 2023-08-30)

主引用文献

Nawaz, M.H.,Ferreira, J.C.,Nedyalkova, L.,Zhu, H.,Carrasco-Lopez, C.,Kirmizialtin, S.,Rabeh, W.M.
The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation.
Biosci.Rep., 38:-, 2018

PubMed Abstract: The high proliferation rate of tumor cells demands high energy and metabolites that are sustained by a high glycolytic flux known as the 'Warburg effect'. The activation and further metabolism of glucose is initiated by hexokinase, a focal point of metabolic regulation. The human hexokinase 2 (HK2) is overexpressed in all aggressive tumors and predominantly found on the outer mitochondrial membrane, where interactions through its N-terminus initiates and maintains tumorigenesis. Here, we report the structure of HK2 in complex with glucose and glucose-6-phosphate (G6P). Structural and biochemical characterization of the mitochondrial conformation reveals higher conformational stability and slow protein unfolding rate () compared with the cytosolic conformation. Despite the active site similarity of all human hexokinases, the N-domain of HK2 is catalytically active but not in hexokinase 1 and 3. Helix-α that protrudes out of the N-domain to link it to the C-domain of HK2 is found to be important in maintaining the catalytic activity of the N-half. In addition, the N-domain of HK2 regulates the stability of the whole enzyme in contrast with the C-domain. Glucose binding enhanced the stability of the wild-type (WT) enzyme and the single mutant D657A of the C-domain, but it did not increase the stability of the D209A mutant of the N-domain. The interaction of HK2 with the mitochondria through its N-half is proposed to facilitate higher stability on the mitochondria. The identification of structural and biochemical differences between HK2 and other human hexokinase isozymes could potentially be used in the development of new anticancer therapies.

PubMed: 29298880
DOI: 10.1042/BSR20171666

実験手法

X-RAY DIFFRACTION (2.45 Å)