4F2A

Crystal structure of cholestryl esters transfer protein in complex with inhibitors

4F2A の概要

• エントリーDOI: 10.2210/pdb4f2a/pdb
• 関連するPDBエントリー: 4EWS
• 分子名称: Cholesteryl ester transfer protein, alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, CHOLESTERYL OLEATE, ... (7 entities in total)
• 機能のキーワード: cholestryl ester transfer protein, high-density lipoprotein, low-density lipoprotein, cholestryl ester transfer protein-inhibitor complex, lipid transport-inhibitor complex, lipid transport/inhibitor
• 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: 56673.26

構造登録者

Liu, S.,Qiu, X. (登録日: 2012-05-07, 公開日: 2012-09-05, 最終更新日: 2024-11-20)

主引用文献

Liu, S.,Mistry, A.,Reynolds, J.M.,Lloyd, D.B.,Griffor, M.C.,Perry, D.A.,Ruggeri, R.B.,Clark, R.W.,Qiu, X.
Crystal structures of cholesteryl ester transfer protein in complex with inhibitors.
J.Biol.Chem., 287:37321-37329, 2012

PubMed Abstract: Human plasma cholesteryl ester transfer protein (CETP) transports cholesteryl ester from the antiatherogenic high-density lipoproteins (HDL) to the proatherogenic low-density and very low-density lipoproteins (LDL and VLDL). Inhibition of CETP has been shown to raise human plasma HDL cholesterol (HDL-C) levels and is potentially a novel approach for the prevention of cardiovascular diseases. Here, we report the crystal structures of CETP in complex with torcetrapib, a CETP inhibitor that has been tested in phase 3 clinical trials, and compound 2, an analog from a structurally distinct inhibitor series. In both crystal structures, the inhibitors are buried deeply within the protein, shifting the bound cholesteryl ester in the N-terminal pocket of the long hydrophobic tunnel and displacing the phospholipid from that pocket. The lipids in the C-terminal pocket of the hydrophobic tunnel remain unchanged. The inhibitors are positioned near the narrowing neck of the hydrophobic tunnel of CETP and thus block the connection between the N- and C-terminal pockets. These structures illuminate the unusual inhibition mechanism of these compounds and support the tunnel mechanism for neutral lipid transfer by CETP. These highly lipophilic inhibitors bind mainly through extensive hydrophobic interactions with the protein and the shifted cholesteryl ester molecule. However, polar residues, such as Ser-230 and His-232, are also found in the inhibitor binding site. An enhanced understanding of the inhibitor binding site may provide opportunities to design novel CETP inhibitors possessing more drug-like physical properties, distinct modes of action, or alternative pharmacological profiles.

PubMed: 22961980
DOI: 10.1074/jbc.M112.380063

実験手法

X-RAY DIFFRACTION (3.11 Å)