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7LHC

NMR Solution Structure of [T20K]kalata B1

Summary for 7LHC
Entry DOI10.2210/pdb7lhc/pdb
NMR InformationBMRB: 30848
DescriptorKalata-B1 (1 entity in total)
Functional Keywordscyclotide, cck motif, knottin, cyclic peptide, plant protein
Biological sourceOldenlandia affinis
Total number of polymer chains1
Total formula weight2945.42
Authors
Harvey, P.J.,Craik, D.J.,Gruber, C.W. (deposition date: 2021-01-22, release date: 2021-10-20, Last modification date: 2024-10-23)
Primary citationHellinger, R.,Muratspahic, E.,Devi, S.,Koehbach, J.,Vasileva, M.,Harvey, P.J.,Craik, D.J.,Grundemann, C.,Gruber, C.W.
Importance of the Cyclic Cystine Knot Structural Motif for Immunosuppressive Effects of Cyclotides.
Acs Chem.Biol., 16:2373-2386, 2021
Cited by
PubMed Abstract: The cyclotide T20K inhibits the proliferation of human immune cells and is currently in clinical trials for multiple sclerosis. Here, we provide novel functional data and mechanistic insights into structure-activity relationships of T20K. Analogs with partial or complete reduction of the cystine knot had loss of function in proliferation experiments. Similarly, an acyclic analog of T20K was inactive in lymphocyte bioassays. The lack of activity of non-native peptide analogs appears to be associated with the ability of cyclotides to interact with and penetrate cell membranes, since cellular uptake studies demonstrated fast fractional transfer only of the native peptide into the cytosol of human immune cells. Therefore, structural differences between cyclic and linear native folded peptides were investigated by NMR to elucidate structure-activity relationships. Acyclic T20K had a less rigid backbone and considerable structural changes in loops 1 and 6 compared to the native cyclic T20K, supporting the idea that the cyclic cystine knot motif is a unique bioactive scaffold. This study provides evidence that this structural motif in cyclotides governs bioactivity, interactions with and transport across biological membranes, and the structural integrity of these peptides. These observations could be useful to understand the structure-activity of other cystine knot proteins due to the structural conservation of the cystine knot motif across evolution and to provide guidance for the design of novel cyclic cysteine-stabilized molecules.
PubMed: 34592097
DOI: 10.1021/acschembio.1c00524
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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