3IIQ

Crystallographic analysis of bacterial signal peptidase in ternary complex with Arylomycin A2 and a beta-sultam inhibitor

Summary for 3IIQ

• Entry DOI: 10.2210/pdb3iiq/pdb
• Related: 1B12 1KN9 1T7D
• Related PRD ID: PRD_000117
• Descriptor: SIGNAL PEPTIDASE I, ARYLOMYCIN A2, 4-[(1,1-dioxido-1,2-thiazetidin-2-yl)carbonyl]morpholine, ... (8 entities in total)
• Functional Keywords: ser/lys dyad, lipopeptide, serine protease, biaryl bridge, morpholino beta-sultam, antibiotic, peptidase, hydrolase-antibiotic-inhibitor complex, hydrolase/antibiotic/inhibitor
• Biological source: ESCHERICHIA COLI; More
• Cellular location: Cell inner membrane; Multi-pass membrane protein: P00803
• Total number of polymer chains: 4
• Total formula weight: 59219.29

Authors

Paetzel, M. (deposition date: 2009-08-03, release date: 2009-09-01, Last modification date: 2023-09-06)

Primary citation

Luo, C.,Roussel, P.,Dreier, J.,Page, M.G.,Paetzel, M.
Crystallographic Analysis of Bacterial Signal Peptidase in Ternary Complex with Arylomycin A2 and a Beta-Sultam Inhibitor.
Biochemistry, 48:8976-, 2009

PubMed Abstract: Bacterial type I signal peptidase (SPase I), an essential membrane-bound endopeptidase with a unique Ser/Lys dyad mechanism, is being investigated as a potential novel antibiotic target. We present here binding and inhibition assays along with crystallographic data that shows that the lipohexapeptide-based natural product arylomycin A2 and the morpholino-beta-sultam derivative (BAL0019193) inhibit SPase I by binding to non-overlapping subsites near the catalytic center. The 2.0 A resolution crystal structure of the soluble catalytic domain of Escherichia coli SPase I (SPase I Delta2-75) in ternary complex with arylomycin A2 and BAL0019193 reveals the position of BAL0019193 adjacent to arylomycin A2 within the SPase I binding site. BAL0019193 binds in a noncovalent manner in close proximity to SPase I residues Ser88, Ser90, Lys145, Asn277, Ala279, and Glu307, as well as atom O45 of arylomycin A2. The binding mode of arylomycin A2 in this 2.0 A resolution ternary complex is compared to that seen in the previous 2.5 A resolution arylomycin A2-SPase cocrystal structure. This work contributes to our understanding of SPase I inhibitor/substrate recognition and should prove helpful in the further development of novel antibiotics based on the inhibition of SPase I.

PubMed: 19655811
DOI: 10.1021/BI9009538

Experimental method

X-RAY DIFFRACTION (2 Å)