Structural basis for plastic glycolipid recognition of the C-type lectin Mincle

Furukawa, Akinori; Shuchi, Yusuke; Wang, Jiaqi; Guillen-Poza, Pablo A; Ishizuka, Shigenari; Kagoshima, Masahiko; Ikeno, Risa; Kumeta, Hiroyuki; Yamasaki, Satoshi; Matsumaru, Takanori; Saitoh, Takashi; Maenaka, Katsumi

doi:10.1016/j.str.2023.05.018

Cited by 3 publications

(3 citation statements)

References 39 publications

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“…This is particularly well illustrated by the dependency of mincle‐induced signaling on oligosaccharides di‐esterized with branched fatty acids, such as trehalose dimycolate (TDM) and phenolic glycolipid‐III (PGL‐III) [57,59,60] . Several X‐ray crystallographic and NMR studies of human and bovine mincle indicated that the interaction with these glycolipids involves Ca 2+ ‐dependent binding of the first glucose, an additional proximal binding site for the second glucose, as well as a hydrophobic grove for lipid binding [54–57,61,62] (Figure 2c). Since these extended recognition interfaces are less conserved, they also provide selectivity, even between closely related CLRs, such as DC‐SIGN and its mouse homologs SIGN‐R1, 2, 3, 4, 5, 7, and 8 [63–65] .…”

Section: Canonical Glycan Bindingmentioning

confidence: 93%

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Secondary Sites of the C‐type Lectin‐Like Fold

Lefèbre,

Falk,

Ning

et al. 2024

Chemistry A European J

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C‐type lectins are a large superfamily of proteins involved in a multitude of biological processes. In particular, their involvement in immunity and homeostasis has rendered them attractive targets for diverse therapeutic interventions. They share a characteristic C‐type lectin‐like domain whose adaptability enables them to bind a broad spectrum of ligands beyond the originally defined canonical Ca2+‐dependent carbohydrate binding. Together with variable domain architecture and high‐level conformational plasticity, this enables C‐type lectins to meet diverse functional demands. Secondary sites provide another layer of regulation and are often intricately linked to functional diversity. Located remote from the canonical primary binding site, secondary sites can accommodate ligands with other physicochemical properties and alter protein dynamics, thus enhancing selectivity and enabling fine‐tuning of the biological response. In this review, we outline the structural determinants allowing C‐type lectins to perform a large variety of tasks and to accommodate the ligands associated with it. Using the six well‐characterized Ca2+‐dependent and Ca2+‐independent C‐type lectin receptors DC‐SIGN, langerin, MGL, dectin‐1, CLEC‐2 and NKG2D as examples, we focus on the characteristics of non‐canonical interactions and secondary sites and their potential use in drug discovery endeavors.

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Section: Canonical Glycan Bindingmentioning

confidence: 93%

“…The acyl chain of the trehalose monobutyrat is not fully resolved but points towards a hydrophobic grove designated as the primary lipid site (3). A second lipid site (4) was also proposed [54–57] …”

Section: Canonical Glycan Bindingmentioning

confidence: 99%

Secondary Sites of the C‐type Lectin‐Like Fold

Lefèbre,

Falk,

Ning

et al. 2024

Chemistry A European J

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“…By the whole experiment, it is expected to identify the ligand binding site in Mincle and determine the K D value of the interaction with ligands, such as glycolipid 1 and glycerolipid. 8 This method is also suitable for the identification of the binding site of a drug without the co-crystallization of a protein and a drug.…”

Section: Expected Outcomesmentioning

confidence: 99%

Protocol to identify the ligand binding site of Mincle using NMR spectroscopy

Furukawa,

Kumeta,

Saitoh

et al. 2024

STAR Protocols

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Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

Noriega,

Corey,

Haanappel

et al. 2024

Preprint

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Macrophage inducible Ca2+-dependent lectin (Mincle) receptor recognizes Mycobacterium tuberculosis glycolipids to trigger an immune response. This host membrane receptor is thus a key player in the modulation of the immune response to infection by M. tuberculosis, and has emerged as a promising target for the development of new vaccines for tuberculosis. The recent development of the Martini 3 force field for coarse-grained (CG) molecular modeling allow the study of interactions of soluble proteins with small ligands but its use for the study of interactions with lipids remains less explored. Here, we present a refined approach detailing a protocol for modeling such interactions at a CG level using the Martini 3 force field. Using this approach, we studied Mincle and identified critical parameters governing ligand recognition, such as loop flexibility and the regulation of hydrophobic groove formation by calcium ions. In addition, we assessed ligand affinity using free energy perturbation calculations. Our results offer mechanistic insight into the interactions between Mincle and glycolipids, providing a basis for rational design of molecules targeting this type of membrane receptors.

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Structural basis for plastic glycolipid recognition of the C-type lectin Mincle

Cited by 3 publications

References 39 publications

Secondary Sites of the C‐type Lectin‐Like Fold

Secondary Sites of the C‐type Lectin‐Like Fold

Protocol to identify the ligand binding site of Mincle using NMR spectroscopy

Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

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