Title : Crystal structure of the human
ecto-5'-nucleotidase (
CD73 ): insights into the regulation of purinergic signaling
Abstract :
- In vertebrates ecto-5'-nucleotidase ( e5NT ) catalyzes the hydrolysis of extracellular AMP to adenosine and represents the major control point for extracellular adenosine levels
- Due to its pivotal role for activation of P1 adenosine receptors , e5NT has emerged as an appealing drug target for treatment of inflammation, chronic pain, hypoxia, and cancer
- Crystal structures of the dimeric human e5NT reveal an extensive 114° conformational switch between the open and closed forms of the enzyme
- The dimerization interface is formed by the C-terminal domains and exhibits inter chain motions of up to 13°
- Complex structures with adenosine and AMPCP indicate that structural control of the domain movement determines the selectivity for monophosphate nucleotides
- Binding modes of nucleotide-derived and flavonoid-based compounds complexed to the C-terminal domain in the open form reveal an additional binding pocket of ∼210 Å(3) that might be explored to design more potent inhibitors
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