Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors
Figure 5
Conformational changes in 380-helix induced by resistant mutations at S165.
a) Superimposition of NAMPT-S165F/GNE-618 complex structure (ribbons colored in cyan) onto a wild-type apo-structure (PDB entry 4KFO, ribbons colored in brown). GNE-618 is shown in sticks, and colored by atom type (carbons in light blue). The inhibitor-binding site is drawn in surface representation, two monomers colored in cyan and green, respectively. S165F is shown in red sticks, which imposes a steric clash onto residue L386 (sticks colored in wheat) of the wild-type structure. The normal PRPP binding mode is illustrated in transparent red spheres. For comparison, a structure of GNE-617 is shown in sticks (carbons in yellow). b) Superimposition of NAMPT-S165F/pRib-GNE-617 complex (ribbons colored in orange) onto the structure of NAMPT-S165F/GNE-617 ribbons colored in cyan). The pRib-GNE-617 molecule is shown in sticks (carbons in brown). GNE-617 is also shown in sticks (carbons in yellow). S165F is shown in red sticks. The resulting 380-helix avoided the steric clash between with Phe165. c) NMN production by wild-type (WT) and mutant NAMPT enzymes in the indicated concentrations of PRPP.