6QBH

Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 33

Summary for 6QBH

• Entry DOI: 10.2210/pdb6qbh/pdb
• Related: 6QBG
• Descriptor: Cathepsin D, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (4~{S},5~{S},9~{S})-5-oxidanyl-4-(phenylmethyl)-9-propan-2-yl-1-oxa-3,8,11-triazacyclodocosane-2,7,10-trione, ... (8 entities in total)
• Functional Keywords: aspartic protease, peptidomimetic inhibitor, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 38382.77

Authors

Brynda, J.,Houstecka, R.,Majer, P.,Mares, M. (deposition date: 2018-12-21, release date: 2020-01-29, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)