| 1. |
- Andersson, David C., 1978-, et al.
(författare)
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Mapping of ligand-binding cavities in proteins
- 2010
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Ingår i: Proteins. - : John Wiley & Sons, Inc. - 0887-3585 .- 1097-0134. ; 78:6, s. 1408-1422
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Tidskriftsartikel (refereegranskat)abstract
- The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterize and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity, and charge). This approach can provide valuable information on the similarities and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterization and mapping of "orphan structures", selection of protein structures for docking studies in structure-based design, and identification of proteins for selectivity screens in drug design programs.
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| 2. |
- Andersson, Ida E, 1982-, et al.
(författare)
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Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:3, s. e17881-
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Tidskriftsartikel (refereegranskat)abstract
- The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.
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| 3. |
- Andersson, Ida E., 1982-, et al.
(författare)
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(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 133:36, s. 14368-14378
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Tidskriftsartikel (refereegranskat)abstract
- The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.
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| 4. |
- Andersson, Ida E., 1982-, et al.
(författare)
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Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins
- 2010
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Ingår i: Organic and biomolecular chemistry. - : RSC Publishing. - 1477-0520 .- 1477-0539. ; 8:13, s. 2931-2940
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Tidskriftsartikel (refereegranskat)abstract
- The glycopeptide CII259-273, a fragment from type II collagen (CII), can induce tolerance in mice susceptible to collagen-induced arthritis (CIA), which is a validated disease model for rheumatoid arthritis (RA). Here, we describe the design and synthesis of a small series of modified CII259-273 glycopeptides with oxazole heterocycles replacing three potentially labile peptide bonds. These glycopeptidomimetics were evaluated for binding to murine CIA-associated A(q) and human RA-associated DR4 class II major histocompatibility complex (MHC) proteins. The oxazole modifications drastically reduced or completely abolished binding to A(q). Two of the glycopeptidomimetics were, however, well tolerated in binding to DR4 and they also induced strong responses by one or two DR4-restricted T-cell hybridomas. This work contributes to the development of an altered glycopeptide for inducing immunological tolerance in CIA, with the long-term goal of developing a therapeutic vaccine for treatment of RA.
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| 5. |
- Palm-Espling, Maria, 1984-, et al.
(författare)
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Determinants for simultaneous binding of copper and platinum to human chaperone Atox1 : hitchhiking not hijacking
- 2013
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Cisplatin (CisPt) is an anticancer agent that has been used for decades to treat a variety of cancers. CisPt treatment causes many side effects due to interactions with proteins that detoxify the drug before reaching the DNA. One key player in CisPt resistance is the cellular copper-transport system involving the uptake protein Ctr1, the cytoplasmic chaperone Atox1 and the secretory path ATP7A/B proteins. CisPt has been shown to bind to ATP7B, resulting in vesicle sequestering of the drug. In addition, we and others showed that the apo-form of Atox1 could interact with CisPt in vitro and in vivo. Since the function of Atox1 is to transport copper (Cu) ions, it is important to assess how CisPt binding depends on Cu-loading of Atox1. Surprisingly, we recently found that CisPt interacted with Cu-loaded Atox1 in vitro at a position near the Cu site such that unique spectroscopic features appeared. Here, we identify the binding site for CisPt in the Cu-loaded form of Atox1 using strategic variants and a combination of spectroscopic and chromatographic methods. We directly prove that both metals can bind simultaneously and that the unique spectroscopic signals originate from an Atox1 monomer species. Both Cys in the Cu-site (Cys12, Cys15) are needed to form the di-metal complex, but not Cys41. Removing Met10 in the conserved metal-binding motif makes the loop more floppy and, despite metal binding, there are no metal-metal electronic transitions. In silico geometry minimizations provide an energetically favorable model of a tentative ternary Cu-Pt-Atox1 complex. Finally, we demonstrate that Atox1 can deliver CisPt to the fourth metal binding domain 4 of ATP7B (WD4), indicative of a possible drug detoxification mechanism.
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