8PKN

CryoEM structure of catalytic domain of human HMG-CoA reductase with its inhibitor atorvastatin

8PKN の概要

• エントリーDOI: 10.2210/pdb8pkn/pdb
• 関連するPDBエントリー: 1hwk 8S6B
• EMDBエントリー: 17748
• 分子名称: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID (2 entities in total)
• 機能のキーワード: reductase, cholesterol biosynthesis, lipitor, atorvastatin, statins, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45817.66

構造登録者

Manikandan, K.,Van Rooyen, J. (登録日: 2023-06-27, 公開日: 2025-01-15, 最終更新日: 2025-03-12)

主引用文献

Karuppasamy, M.,van Rooyen, J.
Cryo-EM structures of apo and atorvastatin-bound human 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Acta Crystallogr.,Sect.F, 81:118-122, 2025

PubMed Abstract: The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) regulates the level of cholesterol by catalysing the formation/production of mevalonate and has therefore become an important pharmaceutical target for coronary heart disease. Here, we report the cryo-EM structure of the catalytic part of the enzyme in the apo form and bound with its inhibitor atorvastatin, a commonly used drug in cardiovascular disease, at resolutions of 2.1 and 2.3 Å, respectively. In the cryo-EM maps, part of the N-domain corresponding to amino acids 439-487 is well ordered and could be modelled completely. Atorvastatin molecules were found to occupy all four active sites of the tetrameric complex, and the binding does not alter the conformation of the protein or the active site. The method described here exploits graphene oxide as an additional support and could be used as an alternative to elucidate the structures of pharmaceutical target compounds that are difficult to co-crystallize with human HMGR and for sparsely available samples in drug discovery.

PubMed: 39976191
DOI: 10.1107/S2053230X25001098

実験手法

ELECTRON MICROSCOPY (2.26 Å)