6MVD

Crystal structure of Lecithin:cholesterol acyltransferase (LCAT) in complex with isopropyl dodec-11-enylfluorophosphonate (IDFP) and a small molecule activator

「6DTJ」から置き換えられました

6MVD の概要

• エントリーDOI: 10.2210/pdb6mvd/pdb
• 分子名称: Phosphatidylcholine-sterol acyltransferase, 2-acetamido-2-deoxy-beta-D-glucopyranose, propan-2-yl hydrogen (R)-ethylphosphonate, ... (7 entities in total)
• 機能のキーワード: lcat, acyltransferase, cholesterol, activator, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 90375.54

構造登録者

Manthei, K.A.,Chang, L.,Tesmer, J.J.G. (登録日: 2018-10-25, 公開日: 2018-12-05, 最終更新日: 2024-11-06)

主引用文献

Manthei, K.A.,Yang, S.M.,Baljinnyam, B.,Chang, L.,Glukhova, A.,Yuan, W.,Freeman, L.A.,Maloney, D.J.,Schwendeman, A.,Remaley, A.T.,Jadhav, A.,Tesmer, J.J.
Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol.
Elife, 7:-, 2018

PubMed Abstract: Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.

PubMed: 30479275
DOI: 10.7554/eLife.41604

実験手法

X-RAY DIFFRACTION (3.1 Å)