6YE1
Human Ecto-5'-nucleotidase (CD73) in complex with the AMPCP derivative A894 (compound 2n in publication) in the closed form (crystal form IV)
Summary for 6YE1
| Entry DOI | 10.2210/pdb6ye1/pdb |
| Descriptor | 5'-nucleotidase, ZINC ION, [(2~{R},3~{S},4~{R},5~{R})-5-[2-chloranyl-6-(cyclopentylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxymethylphosphonic acid, ... (4 entities in total) |
| Functional Keywords | competitive nucleotide inhibitor, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 119710.07 |
| Authors | Scaletti, E.,Strater, N. (deposition date: 2020-03-23, release date: 2021-01-20, Last modification date: 2024-11-06) |
| Primary citation | Sharif, E.U.,Kalisiak, J.,Lawson, K.V.,Miles, D.H.,Newcomb, E.,Lindsey, E.A.,Rosen, B.R.,Debien, L.P.P.,Chen, A.,Zhao, X.,Young, S.W.,Walker, N.P.,Strater, N.,Scaletti, E.R.,Jin, L.,Xu, G.,Leleti, M.R.,Powers, J.P. Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors. J.Med.Chem., 64:845-860, 2021 Cited by PubMed Abstract: Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A and A). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,β-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of , which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile. PubMed: 33399453DOI: 10.1021/acs.jmedchem.0c01835 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.66 Å) |
Structure validation
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