6MHM

Crystal structure of human acid ceramidase in covalent complex with carmofur

Summary for 6MHM

• Entry DOI: 10.2210/pdb6mhm/pdb
• Related PRD ID: PRD_900017
• Descriptor: Acid ceramidase subunit alpha, Acid ceramidase subunit beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: acid ceramidase, acid ceramidase inhibitors, benzoxazolone carboxamides, carmofur, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 92452.01

Authors

Dementiev, A.,Joachimiak, A.,Doan, N. (deposition date: 2018-09-18, release date: 2019-01-23, Last modification date: 2024-10-16)

Primary citation

Dementiev, A.,Joachimiak, A.,Nguyen, H.,Gorelik, A.,Illes, K.,Shabani, S.,Gelsomino, M.,Ahn, E.E.,Nagar, B.,Doan, N.
Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur.
J. Med. Chem., 62:987-992, 2019

PubMed Abstract: Human acid ceramidase (AC) is a lysosomal cysteine amidase, which has received a great deal of interest in recent years as a potential target for the development of new therapeutics against melanoma and glioblastoma tumors. Despite the strong interest in obtaining structural information, only the structures of the apo-AC enzyme in its zymogen and activated conformations are available. In this work, the crystal structure of AC in complex with the covalent carmofur inhibitor is presented. Carmofur is an antineoplastic drug containing an electrophilic carbonyl reactive group that targets the catalytic cysteine. This novel structural data explains the basis of the AC inhibition, provides insights into the enzymatic properties of the protein, and is a great aid toward the structure-based drug design of potent inhibitors for AC, providing the detailed mechanism, which has eluded the scientific community for more than 30 years, of carmofur's mysterious 5-fluorouracil-independent antitumor activity.

PubMed: 30525581
DOI: 10.1021/acs.jmedchem.8b01723

Experimental method

X-RAY DIFFRACTION (2.743 Å)