6QCB

Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 9

6QCB の概要

• エントリーDOI: 10.2210/pdb6qcb/pdb
• 分子名称: Cathepsin D, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: aspartic protease, peptidomimetic inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38907.14

構造登録者

Brynda, J.,Houstecka, R.,Majer, P.,Mares, M. (登録日: 2018-12-27, 公開日: 2020-01-29, 最終更新日: 2024-11-13)

主引用文献

Houstecka, R.,Hadzima, M.,Fanfrlik, J.,Brynda, J.,Pallova, L.,Hanova, I.,Mertlikova-Kaiserova, H.,Lepsik, M.,Horn, M.,Smrcina, M.,Majer, P.,Mares, M.
Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis.
J.Med.Chem., 63:1576-1596, 2020

PubMed Abstract: Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.

PubMed: 32003991
DOI: 10.1021/acs.jmedchem.9b01351

実験手法

X-RAY DIFFRACTION (1.55 Å)