Crystal Structure of Rattus norvegicus Visfatin/PBEF/Nampt in Complex with an FK866-Based Inhibitor

다국어 초록 (Multilingual Abstract)

Visfatin (Nampt/PBEF) plays a pivotal role in the salvage
pathway for NAD+ biosynthesis. Its potent inhibitor, FK866,
causes cellular NAD+ levels to decline, thereby inducing
apoptosis in tumor cells. In an effort to improve the
solubility and binding interactions of FK866, we designed
and synthesized IS001, in which a ribose group is attached
to the FK866 pyridyl ring. Here, we report the crystal structure
of rat visfatin in complex with IS001. Like FK866, IS001
is positioned at the dimer interface, and all of the residues
that interact with IS001 are involved in hydrophobic or π-π-
stacking interactions. However, we were unable to detect
any strong interactions between the added ribose ring of
IS001 and visfatin, which implies that a bulkier modifying
group is necessary for a tight interaction. This study provides
additional structure-based information needed to
optimize the design of visfatin inhibitors.

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