7QGA
Human CD73 (ecto 5'-nucleotidase) in complex with MRS4598 (a 3-methyl-CMPCP derivative, compound 16 in paper) in the open state
Summary for 7QGA
| Entry DOI | 10.2210/pdb7qga/pdb |
| Descriptor | 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | en, e5nt, ecto-nucleotidase, inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 61478.46 |
| Authors | Strater, N. (deposition date: 2021-12-07, release date: 2022-02-16, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 35080883DOI: 10.1021/acs.jmedchem.1c01852 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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