2M7I: Solution structure of a Beta-Hairpin Peptidomimetic antibiotic that targets LptD in Pseudomonas sp

We report structural studies in aqueous solution on backbone cyclic peptides that possess potent antimicrobial activity specifically against Pseudomonas sp. The peptides target the beta-barrel outer membrane protein LptD, which plays an essential role in lipopolysaccharide transport to the outer membrane. The peptide L27-11 contains a 12-residue loop (T(1)W(2)L(3)K(4)K(5)R(6)R(7)W(8)K(9)K(10)A(11)K(12)) linked to a DPro-LPro template. Two related peptides were also studied, one with various Lys to ornithine or diaminobutyric acid substitutions as well as a DLys(6) (called LB-01), and another containing the same loop sequence, but linked to an LPro-DPro template (called LB-02). NMR studies and MD simulations show that L27-11 and LB-01 adopt beta-hairpin structures in solution. In contrast, LB-02 is more flexible and importantly, adopts a wide variety of different backbone conformations, but not beta-hairpin conformations. L27-11 and LB-01 show antimicrobial activity in the nanomolar range against Pseudomonas aeruginosa, whereas LB-02 is essentially inactive. Thus the beta-hairpin structure of the peptide is important for antimicrobial activity. An alanine scan of L27-11 revealed that tryptophan side chains (W(2)/W(8)) displayed on opposite faces of the beta-hairpin represent key groups contributing to antimicrobial activity.
PDB ID: 2M7IDownload
MMDB ID: 113306
PDB Deposition Date: 2013/4/24
Updated in MMDB: 2013/09
Experimental Method:
solution nmr
Similar Structures:
Biological Unit for 2M7I: monomeric; determined by author
Molecular Components in 2M7I
Label Count Molecule
Protein (1 molecule)
Beta-hairpin Peptidomimetic Antibiotic Twl(dab)(orn)(dly)rw(orn)(dab)ak(dpr)p
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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