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<p>Acyl-carrier-protein (ACP) is the principal transporter of fatty acids, coordinating
acyl-transfer among a vast network of diverse enzymes and biochemical processes.
ACP association with protein partners is thought to be exceedingly transient. This
paradigm has posed challenges for understanding the molecular basis for acyl-delivery
and dissociation. During biosynthesis of the lipid A component (endotoxin) of lipopolysaccharides,
ACP shuttles acyl-intermediates thioester-linked to its 4'-phosphopantetheine arm
among four acyltransferases: LpxA, LpxD, LpxL, and LpxM. LpxA and LpxD are essential
cytoplasmic enzymes, which not only provide an excellent model system to study ACP-based
interaction, but also offer an important therapeutic target for development of novel
antibiotics. The current dissertation reports the crystal structures of three forms
of <italic>Escherichia coli</italic> ACP engaging LpxD, which represent stalled substrate
and breakage products along the reaction coordinate. The structures reveal the intricate
interactions at the interface that optimally position ACP for acyl-delivery and directly
involve the pantetheinyl group. Conformational differences among the stalled ACPs
provide the molecular basis for the association-dissociation process. An unanticipated
conformational shift of 4'-phosphopantetheine groups within the LpxD catalytic chamber
reveals an unprecedented role of ACP in product release. Moreover, the crystal structure
of <italic>E. coli</italic> LpxA in complex with one form of ACP (holo-ACP) is presented.
The structure reveals three molecules of holo-ACP localize to the C-terminal domain
of the LpxA homotrimer, and shows the functional role of this domain is two-fold:
ACP recognition and nucleotide binding of UDP-GlcNAc. A comparison with the LpxD:ACP
complexes uncovers that ACP utilizes different surface residues for recognition even
amongst closely related acyltransferases, yet still relies on "electrostatic steering"
for docking to its enzyme partner. Insights gleaned from the presented structures
have provided not only a better understanding of ACP interaction with acyltransferases,
but also has identified the "drugable molecular landscape" for the development of
novel antibiotics against infective bacteria.</p>
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