Structural Basis for Simvastatin Competitive Antagonism of Complement Receptor 3

Jensen, Maria Risager; Bajic, Goran; Zhang, Xianwei; Laustsen, Anne Kjær; Koldsø, Heidi; Skeby, Katrine Kirkeby; Schiøtt, Birgit; Andersen, Gregers Rom; Vorup-Jensen, Thomas

doi:10.1074/jbc.m116.732222

Cited by 28 publications

(33 citation statements)

References 66 publications

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“…A third consequence of the anion chelation model suggest that at least carboxylates would be ligands for the α M I and α X I irrespective of their “mounting.” It was already shown that acetate and propionate inhibited CR4 ligand binding as efficiently as glutamate ( 88 ). This was further confirmed by structural studies over the interaction between the cholesterol-lowering drug simvastatin and the α M I ( 83 ). Interestingly, while the binding between the simvastatin carboxylate (Figure 8A ) and MIDAS Mg 2+ is relatively stable and almost fixed in geometry as discussed above (Section Structure of CR3 and CR4 ectodomains and Figures 3C,D ), both the molecular dynamics calculations and the lack of resolution of the simvastatin decalin ring in XRC point to rotation of other parts of this ligand when it is chelated to the MIDAS ( 83 ) (Figure 8B ).…”

Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 64%

“… Structural comparison of ligated α M I. (A–F) By use of XRC, the α M I has been characterized in complex with (A,B) C3d [4M76; ( 14 )], (C,D) simvastatin [4XW2; ( 83 )], and (E,F) the ligand-mimicking antibody mAb 107 [3QA3; ( 84 )]. For each complex (A,C,D) the corresponding MIDAS arrangement is indicated with the external ligand for the metal ion coordination sphere (B,D,F) .…”

Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 99%

“…A robust solution to analyzing such experimental data has been provided by Schuck et al with an algorithm enabling determination of the minimal ensemble of 1:1 reactions required to explain the experimental data set ( 125 , 126 ). This algorithm has now been applied to analysis of multiple ligands ( 14 , 83 , 86 – 88 , 127 , 128 ). Typically, the experimental design used the ligand coupled onto surfaces with the I domains applied in the flow stream.…”

Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 99%

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Structural Immunology of Complement Receptors 3 and 4

2018

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Complement receptors (CR) 3 and 4 belong to the family of beta-2 (CD18) integrins. CR3 and CR4 are often co-expressed in the myeloid subsets of leukocytes, but they are also found in NK cells and activated T and B lymphocytes. The heterodimeric ectodomain undergoes considerable conformational change in order to switch the receptor from a structurally bent, ligand-binding in-active state into an extended, ligand-binding active state. CR3 binds the C3d fragment of C3 in a way permitting CR2 also to bind concomitantly. This enables a hand-over of complement-opsonized antigens from the cell surface of CR3-expressing macrophages to the CR2-expressing B lymphocytes, in consequence acting as an antigen presentation mechanism. As a more enigmatic part of their functions, both CR3 and CR4 bind several structurally unrelated proteins, engineered peptides, and glycosaminoglycans. No consensus motif in the proteinaceous ligands has been established. Yet, the experimental evidence clearly suggest that the ligands are primarily, if not entirely, recognized by a single site within the receptors, namely the metal-ion dependent adhesion site (MIDAS). Comparison of some recent identified ligands points to CR3 as inclined to bind positively charged species, while CR4, by contrast, binds strongly negative-charged species, in both cases with the critical involvement of deprotonated, acidic groups as ligands for the Mg2+ ion in the MIDAS. These properties place CR3 and CR4 firmly within the realm of modern molecular medicine in several ways. The expression of CR3 and CR4 in NK cells was recently demonstrated to enable complement-dependent cell cytotoxicity toward antibody-coated cancer cells as part of biological therapy, constituting a significant part of the efficacy of such treatment. With the flexible principles of ligand recognition, it is also possible to propose a response of CR3 and CR4 to existing medicines thereby opening a possibility of drug repurposing to influence the function of these receptors. Here, from advances in the structural and cellular immunology of CR3 and CR4, we review insights on their biochemistry and functions in the immune system.

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Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 64%

Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 99%

Section: The Structure Conformational Regulation and Ligand Recognimentioning

confidence: 99%

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Structural Immunology of Complement Receptors 3 and 4

2018

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“…Linear drift corrections were applied if necessary, using an average of the background drift before and after injection. The two-dimensional fits were made on the MATLAB 2012a platform (Mathworks) using the fitting tool EVILFIT version 3 software 46,47 to determine the distribution of binding kinetics. The following input values were used fitting the binding curves: Injection start time: Concentrations: 20 nM, 100 nM, 300 nM, 1000nM and 3000 nM, Start injection: t=0 s, End injection: t=800 s, Fit binding phase from: t=2s, Fit binding phase to: t=798 s, Fit dissociation phase from: t=1400 s, Fit dissociation phase to: 2400 s.…”

Section: Spr Data Analysismentioning

confidence: 99%

Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association

Mohammad‐Beigi

Hayashi

Zeuthen

et al. 2020

Preprint

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The current understanding of the biological identity that nanoparticles may acquire in a given biological milieu is mostly inferred from the hard component of the protein corona (HC). The composition of soft corona (SC) proteins and their biological relevance have remained elusive due to the lack of analytical separation methods. Here, we identified a set of specific corona proteins with weak interactions at silica and polystyrene nanoparticles by using an in situ click-chemistry reaction. We show that these SC proteins are present also in the HC, but are specifically enriched after the capture, suggesting that the main distinction between HC and SC is the differential binding strength of the same proteins. Interestingly, the weakly interacting proteins in the SC are revealed as modulators of nanoparticle-cell association, in spite of their short residence time. We therefore highlight that weak interactions of proteins at nanoparticles should be considered when evaluating nano-bio interfaces.

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“…The human α-I domain (CD11b-I) was expressed recombinantly, independently of the other integrin subunits (13), and to date 13 crystal structures of CD11b-I in complex with natural ligands, antagonists, antibodies, or alone, have been solved (13)(14)(15)(16)(17)(18)(19)(20). However, despite the critical role of CD11b-I in the immune system of different mammals (21), all available crystal structures were obtained with the human CD11b-I (huCD11b-I).…”

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confidence: 99%

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

Trstenjak

Milić

Graewert

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Host–pathogen interactions are central to understanding microbial pathogenesis. The staphylococcal pore-forming cytotoxins hijack important immune molecules but little is known about the underlying molecular mechanisms of cytotoxin–receptor interaction and host specificity. Here we report the structures of a staphylococcal pore-forming cytotoxin, leukocidin GH (LukGH), in complex with its receptor (the α-I domain of complement receptor 3, CD11b-I), both for the human and murine homologs. We observe 2 binding interfaces, on the LukG and the LukH protomers, and show that human CD11b-I induces LukGH oligomerization in solution. LukGH binds murine CD11b-I weakly and is inactive toward murine neutrophils. Using a LukGH variant engineered to bind mouse CD11b-I, we demonstrate that cytolytic activity does not only require binding but also receptor-dependent oligomerization. Our studies provide an unprecedented insight into bicomponent leukocidin–host receptor interaction, enabling the development of antitoxin approaches and improved animal models to explore these approaches.

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Structural Basis for Simvastatin Competitive Antagonism of Complement Receptor 3

Cited by 28 publications

References 66 publications

Structural Immunology of Complement Receptors 3 and 4

Structural Immunology of Complement Receptors 3 and 4

Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

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