title: Mechanism for recognition of an unusual mycobacterial glycolipid by the macrophage receptor mincle.
abstract: Binding of the macrophage lectin mincle to trehalose dimycolate, a key glycolipid virulence factor on the surface of Mycobacterium tuberculosis and Mycobacterium bovis, initiates responses that can lead both to toxicity and to protection of these pathogens from destruction. Crystallographic structural analysis, site-directed mutagenesis, and binding studies with glycolipid mimics have been used to define an extended binding site in the C-type carbohydrate recognition domain (CRD) of bovine mincle that encompasses both the headgroup and a portion of the attached acyl chains. One glucose residue of the trehalose Glcα1-1Glcα headgroup is liganded to a Ca(2+) in a manner common to many C-type CRDs, whereas the second glucose residue is accommodated in a novel secondary binding site. The additional contacts in the secondary site lead to a 36-fold higher affinity for trehalose compared with glucose. An adjacent hydrophobic groove, not seen in other C-type CRDs, provides a docking site for one of the acyl chains attached to the trehalose, which can be targeted with small molecule analogs of trehalose dimycolate that bind with 52-fold higher affinity than trehalose. The data demonstrate how mincle bridges between the surfaces of the macrophage and the mycobacterium and suggest the possibility of disrupting this interaction. In addition, the results may provide a basis for design of adjuvants that mimic the ability of mycobacteria to stimulate a response to immunization that can be employed in vaccine development.
authors: From the Departments of Structural Biology and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 and.
authors: Hadar
authors: H
authors: Feinberg
authors: Sabine A F
authors: SA
authors: Jégouzo
authors: Thomas J W
authors: TJ
authors: Rowntree
authors: Yue
authors: Y
authors: Guan
authors: Matthew A
authors: MA
authors: Brash
authors: Maureen E
authors: ME
authors: Taylor
authors: William I
authors: WI
authors: Weis
authors: Kurt
authors: K
authors: Drickamer
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D005947:Glucose / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D009161:Mycobacterium / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D014199:Trehalose / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D006017:Glycolipids; D037181:Lectins, C-Type; D008024:Ligands; D011971:Receptors, Immunologic; D014199:Trehalose; D005947:Glucose
keywords: CLEC4E; Carbohydrate-binding Protein; Cord Factor; Crystal Structure; Glycobiology; Glycolipids; Mycobacterium tuberculosis
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