7QGA

Human CD73 (ecto 5'-nucleotidase) in complex with MRS4598 (a 3-methyl-CMPCP derivative, compound 16 in paper) in the open state

7QGA の概要

• エントリーDOI: 10.2210/pdb7qga/pdb
• 分子名称: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: en, e5nt, ecto-nucleotidase, inhibitor, hydrolase
• 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: 61478.46

構造登録者

Strater, N. (登録日: 2021-12-07, 公開日: 2022-02-16, 最終更新日: 2024-01-31)

主引用文献

Scortichini, M.,Idris, R.M.,Moschutz, S.,Keim, A.,Salmaso, V.,Dobelmann, C.,Oliva, P.,Losenkova, K.,Irjala, H.,Vaittinen, S.,Sandholm, J.,Yegutkin, G.G.,Strater, N.,Junker, A.,Muller, C.E.,Jacobson, K.A.
Structure-Activity Relationship of 3-Methylcytidine-5'-alpha , beta-methylenediphosphates as CD73 Inhibitors.
J.Med.Chem., 65:2409-2433, 2022

PubMed Abstract: We recently reported -substituted 3-methylcytidine-5'-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 ; = 0.673 nM) and 4-iodo (MRS4620 ; = 0.436 nM) substitution of the -benzyloxy group decreased by ∼20-fold. Primary alkylamine derivatives coupled through a -amido group with a varying methylene chain length ( and ) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group ( configuration) binds to the same region (between the C-terminal and N-terminal domains) as -benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by -benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.

PubMed: 35080883
DOI: 10.1021/acs.jmedchem.1c01852

実験手法

X-RAY DIFFRACTION (1.5 Å)