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October 2000
Vol. 3, No. 8, p. 18.

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Bound to be trouble

A new crystal structure could lead to improved drugs against enteropathogenic E. coli (EPEC), a significant cause of infant mortality worldwide, and enterohemorrhagic E. coli, a major food pathogen. Both are members of a class of organisms called attaching and effacing pathogens, which gain a foothold on the surface of target cells by recruiting the cell’s own structural proteins to form a pedestal. From atop that perch, the pathogens continue the infection process, reproducing and ultimately destroying the cell.

schematic diagram of bacterial binding
Bacterial binding. The bacterium/host-cell interface is mediated by interactions between the bacterial proteins intimin and Tir. (Adapted from Luo et. al Nature 2000, 405, 1073–1077.)
The bacteria operate by first injecting into the cell a protein called translocated intimin receptor (Tir). The bacterial membrane-bound protein intimin then binds to Tir to form a tight link between pathogen and cell. Tir, meanwhile, sets to work recruiting cytoskeletal actin, using it to build the external pedestal.

“That’s what makes [Tir] such a nice drug or vaccine candidate. You wouldn’t want to interfere with a mammalian receptor, but because the receptor is bacterial, it’s an ideal one to target,” says Natalie Strynadka, assistant professor of biochemistry at the University of British Columbia (Vancouver). Her group determined the crystal structure of EPEC intimin linked to the extracellular domain of Tir, which spans the cell membrane as shown (Nature 2000, 405, 1073–1077).

The crystal structure shows that the interaction occurs between an intimin dimer and a Tir dimer, with extended hydrophobic contacts that are multivalent, so that several contacts can keep the large bacteria tightly bound to the cell.

The structure could also have wide applicability. “There are approximately 12 Tirs that have been sequenced from different species. [The structure] shows that the region of the Tir that is forming the complex with intimin is one of the most conserved regions in the [protein]. If we design a peptide analogue that mimics this hairpin element that is very conserved, we hope it will be relatively universal [in its activity],” says Strynadka. Similarly, vaccines designed using this element could protect against multiple species, potentially stopping a wide variety of infections before they get started.


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