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- Hedenström, Mattias, et al.
(författare)
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Conformations and Receptor Activity of Desmopressin Analogues, Which Contain -Turn Mimetics or a [CH2O] Isostere
- 2002
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 45:12, s. 2501-11
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Tidskriftsartikel (refereegranskat)abstract
- Three analogues of the antidiuretic drug desmopressin ([1-desamino,8-D-arginine]vasopressin) have been prepared. In two of these, -turn mimetics based on a morpholin-3-one framework have been inserted instead of residues Phe3-Asn5, whereas the third analogue has a methylene ether isostere in place of the amide bond between residues 3 and 4. The three analogues were used to probe if the structure determined for desmopressin in aqueous solution, which contains an inverse -turn centered around Gln4, is important in interactions with the vasopressin V2 receptor. Conformational studies revealed that the analogues that contain either an inverse -turn mimetic or a methylene ether isostere mimicked the conformation of desmopressin fairly well and very well, respectively. Despite this, the analogues displayed only very low agonistic activities at the vasopressin V2 receptor. Consequently, an inverse -turn involving residues Phe3-Asn5 does not appear to be important when desmopressin is bound to the V2 receptor. In addition, it was concluded that the amide bond between Phe3 and Gln4 in desmopressin is crucial for interactions with the antidiuretic V2 receptor.
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| 2. |
- Tengel, Tobias, et al.
(författare)
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Conformational analysis by CD and NMR spectroscopy of a peptide encompassing the amphipathic domain of YopD from Yersinia
- 2002
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 269:15, s. 3659-3668
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Tidskriftsartikel (refereegranskat)abstract
- To establish an infection, Yersinia pseudotuberculosis utilizes a plasmid-encoded type III secretion machine that permits the translocation of several anti-host factors into the cytosol of target eukaryotic cells. Secreted YopD is essential for this process. Pre-secretory stabilization of YopD is mediated by an interaction with its cognate chaperone, LcrH. YopD possesses LcrH binding domains located in the N-terminus and in a predicted amphipathic domain located near the C-terminus. This latter domain is also critical for Yersinia virulence. In this study, we designed synthetic peptides encompassing the C-terminal amphipathic domain of YopD. A solution structure of YopD278−300, a peptide that strongly interacted with LcrH, was obtained by NMR methods. The structure is composed of a well-defined amphipathic α helix ranging from Phe280 to Tyr291, followed by a type I β turn between residues Val292 and His295. The C-terminal truncated peptides, YopD278−292 and YopD271−292, lacked helical structure, implicating the β turn in helix stability. An interaction between YopD278−300 and its cognate chaperone, LcrH, was observed by NMR through line-broadening effects and chemical shift differences between the free peptide and the peptide–LcrH complex. These effects were not observed for the unstructured peptide, YopD278−292, which confirms that the α helical structure of the YopD amphipathic domain is a critical binding region of LcrH.
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