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11.
Yen-Hua Huang Qingdan Du Zhihao Jiang Gordon J. King Brett M. Collins Conan K. Wang David J. Craik 《Molecules (Basel, Switzerland)》2021,26(18)
Cyclotides have attracted great interest as drug design scaffolds because of their unique cyclic cystine knotted topology. They are classified into three subfamilies, among which the bracelet subfamily represents the majority and comprises the most bioactive cyclotides, but are the most poorly utilized in drug design applications. A long-standing challenge has been the very low in vitro folding yields of bracelets, hampering efforts to characterize their structures and activities. Herein, we report substantial increases in bracelet folding yields enabled by a single point mutation of residue Ile-11 to Leu or Gly. We applied this discovery to synthesize mirror image enantiomers and used quasi-racemic crystallography to elucidate the first crystal structures of bracelet cyclotides. This study provides a facile strategy to produce bracelet cyclotides, leading to a general method to easily access their atomic resolution structures and providing a basis for development of biotechnological applications. 相似文献
12.
D.J. Craik 《Physics letters. A》1984,103(3):93-94
Magnetostatic solutions may be obtained by using Laplace's equation in finite difference form. The boundary equations are of primary importance and even these have been put forward as special forms of Laplace's equation. They can be derived in what appears to be a simpler and more flexible manner by assuming that Poisson's equation applies at the interface for both scalar and vector potentials. 相似文献
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Chu F Mahrus S Craik CS Burlingame AL 《Journal of the American Chemical Society》2006,128(32):10362-10363
Chemical cross-linking followed by identification of the cross-linked residues by mass spectrometry provides structural information on protein interaction surfaces. Nevertheless, accurate analysis of the digested, cross-linked proteins is often challenging. Herein, we describe a novel strategy that relies on the use of affinity-tagged cross-linkers and isotope coding on the cross-linker-modified species. Incorporation of O16 or O18 during the hydrolysis of the cross-linkers results in a characteristic "doublet" for the undesired products of a half-cross-linking reaction. Therefore, genuine cross-linked peptides are readily distinguished for further structural analysis. This strategy permits a sensitive and facile analysis on a dimeric protease inhibitor, ecotin, showing general applicability to other protein assemblies. 相似文献
16.
The cyclotides are a family of small disulfide rich proteins that have a cyclic peptide backbone and a cystine knot formed by three conserved disulfide bonds. The combination of these two structural motifs contributes to the exceptional chemical, thermal and enzymatic stability of the cyclotides, which retain bioactivity after boiling. They were initially discovered based on native medicine or screening studies associated with some of their various activities, which include uterotonic action, anti-HIV activity, neurotensin antagonism, and cytotoxicity. They are present in plants from the Rubiaceae, Violaceae and Cucurbitaceae families and their natural function in plants appears to be in host defense: they have potent activity against certain insect pests and they also have antimicrobial activity. There are currently around 50 published sequences of cyclotides and their rate of discovery has been increasing over recent years. Ultimately the family may comprise thousands of members. This article describes the background to the discovery of the cyclotides, their structural characterization, chemical synthesis, genetic origin, biological activities and potential applications in the pharmaceutical and agricultural industries. Their unique topological features make them interesting from a protein folding perspective. Because of their highly stable peptide framework they might make useful templates in drug design programs, and their insecticidal activity opens the possibility of applications in crop protection. 相似文献
17.
Andrew M. White Simon J. de Veer Guojie Wu Peta J. Harvey Kuok Yap Gordon J. King Joakim E. Swedberg Conan K. Wang Ruby H. P. Law Thomas Durek David J. Craik 《Angewandte Chemie (International ed. in English)》2020,59(28):11273-11277
Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole‐bridged peptides also displayed superior half‐lives in liver S9 stability assays compared to disulfide‐bridged peptides. This work establishes a foundation for the application of 1,5‐disubstituted 1,2,3‐triazoles as disulfide mimetics. 相似文献
18.
Dr. Andrew M. White Dr. Simon J. de Veer Guojie Wu Dr. Peta J. Harvey Kuok Yap Dr. Gordon J. King Dr. Joakim E. Swedberg Dr. Conan K. Wang Dr. Ruby H. P. Law Dr. Thomas Durek Prof. David J. Craik 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(28):11369-11373
Ruthenium-catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics. 相似文献
19.
Cyclotides are head-to-tail cyclic peptides that contain a cystine knot motif built from six conserved cysteine residues. They occur in plants of the Rubiaceae, Violaceae, Cucurbitaceae, and Fabaceae families and, aside from their natural role in host defense, have a range of interesting pharmaceutical activities, including anti-HIV activity. The variation seen in sequences of their six backbone loops has resulted in cyclotides being described as a natural combinatorial template. Their exceptional stability and resistance to enzymatic degradation has led to their use as scaffolds for peptide-based drug design. To underpin such applications, methods for the chemical synthesis of cyclotides have been developed and are described here. Cyclization using thioester chemistry has been instrumental in the synthesis of cyclotides for structure-activity studies. This approach involves a native chemical ligation reaction between an N-terminal Cys and a C-terminal thioester in the linear cyclotide precursor. Since cyclotides contain six Cys residues their syntheses can be designed around any of six linear precursors, thus providing flexibility in synthesis. The ease with which cyclotides fold, despite their topologically complex knot motif, as well as the ability to introduce combinatorial variation in the loops, makes cyclotides a promising drug-design scaffold. 相似文献
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