Structure of undecaprenyl pyrophosphate synthase from Acinetobacter baumannii

Abstract

Undecaprenyl pyrophosphate (UPP) is an important carrier of the oligosaccharide component in peptidoglycan synthesis. Inhibition of UPP synthase (UPPS) may be an effective strategy in combating the pathogen Acinetobacter baumannii, which has evolved to be multidrug-resistant. Here, A. baumannii UPPS (AbUPPS) was cloned, expressed, purified and crystallized, and its structure was determined by X-ray diffraction. Each chain of the dimeric protein folds into a central -sheet with several surrounding -helices, including one at the C-terminus. In the active site, two molecules of citrate interact with the side chains of the catalytic aspartate and serine. These observations may provide a structural basis for inhibitor design against AbUPPS.

Structural Characterization of Full-Length Human Dehydrodolichyl Diphosphate Synthase Using an Integrative Computational and Experimental Approach

“…The cis -prenyltransferase domain was modeled by comparative modeling [20] using Z,Z-farnesyl diphosphate synthase (PDB 5hxn [21], sequence identity 41%) and undecaprenyl pyrophosphate synthase (PDB 6acs [22], sequence identity 35%) as templates. The C-terminal domain (residues 261–340) was modeled by RaptorX-Contact, which is using co-evolutionary information to predict residue–residue contacts [23].…”

Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria

“…The side-chain guanidino moiety of Arg162 is well placed to form a salt bridge with Asp202 (2.8 Å) from the adjacent monomer and also shows the potential for a cation−π interaction with Trp221 (Figure c), while Arg214 is well positioned to form a salt bridge with Glu227 (2.8 Å) from the adjacent monomer in addition to its role in binding C 15 PP (Figure d). Of particular note is Arg256, a residue that was recently proposed to play a role in substrate binding and active site formation based on comparisons to other cis -prenyltransferases; however, our crystal structure, combined with coevolutionary analysis, suggests that the role of Arg256 is rather to form a conserved salt bridge with Glu212 (2.7 Å) of the counter subunit, further contributing to the dimerization interface (Figure d).…”

Cocktailed fragment screening by X-ray crystallography of the antibacterial target undecaprenyl pyrophosphate synthase from Acinetobacter baumannii

“…PDB entry 6acs (Ko et al, 2018) describes the structural features of Ab-UppS with bound citrate in a higher symmetry form than that observed here. Both structures presented here show the physiological dimer as the asymmetric unit, but the active-site pocket of protein chain B has significantly less well defined electron density than that of chain A, lacking residues 33-49, and no fragments were fitted into chain B.…”