4MWO

Crystal structure of human mitochondrial 5'(3')-deoxyribonucleotidase in complex with the inhibitor CPB-T

Summary for 4MWO

• Entry DOI: 10.2210/pdb4mwo/pdb
• Descriptor: 5'(3')-deoxyribonucleotidase, mitochondrial, 1-{3,5-O-[(4-carboxyphenyl)(phosphono)methylidene]-2-deoxy-beta-D-threo-pentofuranosyl}-5-methylpyrimidine-2,4(1H,3H)-dione, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: 5'-nucleotidase, protein conformation, dephosphorylation, phosphorylation, had-like, mitochondia, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion: Q9NPB1
• Total number of polymer chains: 1
• Total formula weight: 24072.17

Authors

Pachl, P.,Rezacova, P.,Brynda, J. (deposition date: 2013-09-25, release date: 2014-09-10, Last modification date: 2023-09-20)

Primary citation

Simak, O.,Pachl, P.,Fabry, M.,Budesinsky, M.,Jandusik, T.,Hnizda, A.,Sklenickova, R.,Petrova, M.,Veverka, V.,Rezacova, P.,Brynda, J.,Rosenberg, I.
Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.
Org.Biomol.Chem., 12:7971-7982, 2014

PubMed Abstract: This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K = 6.60 μM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.

PubMed: 25178098
DOI: 10.1039/c4ob01332h

Experimental method

X-RAY DIFFRACTION (1.67 Å)