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BETA
Brännström, Kristoffer
Alternative names
Publications (10 of 40) Show all publications
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-06-13Bibliographically approved
Zhang, J., Grundström, C., Brännström, K., Iakovleva, I., Lindberg, M. J., Olofsson, A., . . . Sauer-Eriksson, A. E. (2018). Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals. Environmental Science and Technology, 52(20), 11865-11874
Open this publication in new window or tab >>Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals
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2018 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 52, no 20, p. 11865-11874Article in journal (Refereed) Published
Abstract [en]

Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here, we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream (Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, in particular, the polar TDCs (>500-fold lower affinity). Crystal structures of the seabream TTR TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand binding. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-153704 (URN)10.1021/acs.est.8b03581 (DOI)000447816100046 ()30226982 (PubMedID)
Funder
Swedish Research Council Formas, 210-2012-131Swedish Research Council, 521-2011-6427Swedish Research Council, 2015-03607
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Brännström, K., Gharibyan, A. L., Islam, T., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips. Data in Brief, 19, 1166-1170
Open this publication in new window or tab >>Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips
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2018 (English)In: Data in Brief, E-ISSN 2352-3409, Vol. 19, p. 1166-1170Article in journal (Refereed) Published
Abstract [en]

We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1].

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-149049 (URN)10.1016/j.dib.2018.05.129 (DOI)000449869100149 ()30228999 (PubMedID)2-s2.0-85047834173 (Scopus ID)
Note

Refers to: Kristoffer Brännström, Tohidul Islam, Anna L. Gharibyan, Irina Iakovleva, Lina Nilsson, Cheng Choo Lee, Linda Sandblad, Annelie Pamrén, Anders Olofsson. The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, Volume 430, Issue 13, 22 June 2018, Pages 1940-1949

Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2019-02-04Bibliographically approved
Kulén, M., Lindgren, M., Hansen, S., Cairns, A. G., Grundström, C., Begum, A., . . . Almqvist, F. (2018). Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes. Journal of Medicinal Chemistry, 61(9), 4165-4175
Open this publication in new window or tab >>Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4165-4175Article in journal (Refereed) Published
Abstract [en]

Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-148830 (URN)10.1021/acs.jmedchem.8b00289 (DOI)000432204800027 ()29667825 (PubMedID)2-s2.0-85046422455 (Scopus ID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-08-28Bibliographically approved
Brännström, K., Islam, T., Gharibyan, A. L., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, 430(13), 1940-1949
Open this publication in new window or tab >>The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1940-1949Article in journal (Refereed) Published
Abstract [en]

Fibril formation of the amyloid-β peptide (Aβ) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of Aβ are observed in vivo, but Aβ1-40 and Aβ1-42 are the dominant forms. The fibril architectures of Aβ1-40 and Aβ1-42 differ and Aβ1-42 assemblies are generally considered more pathogenic. We show here that monomeric Aβ1-42 can be cross-templated and incorporated into the ends of Aβ1-40 fibrils, while incorporation of Aβ1-40 monomers into Aβ1-42 fibrils is very poor. We also show that via cross-templating incorporated Aβ monomers acquire the properties of the parental fibrils. The suppressed ability of Aβ1-40 to incorporate into the ends of Aβ1-42 fibrils and the capacity of Aβ1-42 monomers to adopt the properties of Aβ1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of Aβ1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents Aβ1-40 from adopting the fibrillar properties of Aβ1-42 and exposes that the transfer of properties between amyloid-β fibrils are determined by their path of formation.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Aβ, Cross-templating, Fibril, Surface Plasmon resonance, Thioflavin-T
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148050 (URN)10.1016/j.jmb.2018.05.001 (DOI)29751013 (PubMedID)2-s2.0-85047103029 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-06-14Bibliographically approved
Nilsson, L., Pamrén, A., Islam, T., Brännström, K., Golchin, S. A., Pettersson, N., . . . Olofsson, A. (2018). Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates. Journal of Molecular Biology, 430(17), 2722-2733
Open this publication in new window or tab >>Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 17, p. 2722-2733Article in journal (Refereed) Published
Abstract [en]

The pathological Aβ aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Aβ, Surface Plasmon Resonance, Thioflavin-T, amyloid, transthyretin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148930 (URN)10.1016/j.jmb.2018.06.005 (DOI)000441645300013 ()29890120 (PubMedID)
Funder
The Dementia Association - The National Association for the Rights of the DementedThe Kempe FoundationsSwedish Research CouncilMagnus Bergvall FoundationTorsten Söderbergs stiftelse
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-09-05Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Brännström, K., Islam, T., Sandblad, L. & Olofsson, A. (2017). The role of histidines in amyloid β fibril assembly. FEBS Letters, 591(8), 1167-1175
Open this publication in new window or tab >>The role of histidines in amyloid β fibril assembly
2017 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 591, no 8, p. 1167-1175Article in journal (Refereed) Published
Abstract [en]

Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH.

Keywords
abeta, amyloid, fibril, histidine, stability, surface plasmon resonance
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-133486 (URN)10.1002/1873-3468.12616 (DOI)000400968800009 ()28267202 (PubMedID)
Note

Alternative title: The role of histidines in amyloid beta fibril assembly

Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2018-06-09Bibliographically approved
Nilsson, L., Larsson, A., Begum, A., Iakovleva, I., Carlsson, M., Kristoffer, B., . . . Olofsson, A. (2016). Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity. PLoS ONE, 11(4), Article ID e0153112.
Open this publication in new window or tab >>Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153112Article in journal (Refereed) Published
Abstract [en]

Amyloid formation of the plasma protein transthyretin (TTR) has been linked to familial amyloid polyneuropathy and senile systemic amyloidosis. Binding of ligands within its natural hormone binding site can stabilize the tetrameric structure and impair amyloid formation. We have recently shown that the flavonoid luteolin stabilizes TTR in human plasma with a very high selectivity. Luteolin, however, is inactivated in vivo via glucuronidation for which the preferred site is the hydroxy group at position 7 on its aromatic A-ring. We have evaluated the properties of two luteolin variants in which the 7-hydroxy group has been exchanged for a chlorine (7-Cl-Lut) or a methoxy group (7-MeO-Lut). Using an in vitro model, based on human liver microsomes, we verified that these modifications increase the persistence of the drug. Crystal structure determinations show that 7-Cl-Lut binds similarly to luteolin. The larger MeO substituent cannot be accommodated within the same space as the chlorine or hydroxy group and as a result 7-MeO-Lut binds in the opposite direction with the methoxy group in position 7 facing the solvent. Both 7-Cl-Lut and 7-MeO-Lut qualify as high-affinity binders, but in contrast to luteolin, they display a highly non-specific binding to other plasma components. The binding of the two conformations and the key-interactions to TTR are discussed in detail. Taken together, these results show a proof-of-concept that the persistence of luteolin towards enzymatic modification can be increased. We reveal two alternative high-affinity binding modes of luteolin to TTR and that modification in position 7 is restricted only to small substituents if the original orientation of luteolin should be preserved. In addition, the present work provides a general and convenient method to evaluate the efficacy of TTR-stabilizing drugs under conditions similar to an in vivo environment.

Place, publisher, year, edition, pages
Public Library Science, 2016
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-119997 (URN)10.1371/journal.pone.0153112 (DOI)000373603500101 ()27050398 (PubMedID)
Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2018-06-07Bibliographically approved
Moonens, K., Gideonsson, P., Subedi, S., Bugaytsova, J., Romao, E., Mendez, M., . . . Remaut, H. (2016). Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host and Microbe, 19(1), 55-66
Open this publication in new window or tab >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, no 1, p. 55-66Article in journal (Refereed) Published
Abstract [en]

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)
Available from: 2016-04-04 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
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