7p2d

Structure of alphaMbeta2/Cd11bCD18 headpiece in complex with a nanobodyStructure of alphaMbeta2/Cd11bCD18 headpiece in complex with a nanobody

Structural highlights 7p2d is a 3 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.2Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ITAM_HUMAN Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:609939. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Function ITAM_HUMAN Integrin alpha-M/beta-2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles. It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin alpha-M/beta-2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. Publication Abstract from PubMed The integrin receptor alphaMbeta2 mediates phagocytosis of complement-opsonized objects, adhesion to the extracellular matrix, and transendothelial migration of leukocytes. However, the mechanistic aspects of alphaMbeta2 signaling upon ligand binding are unclear. Here, we present the first atomic structure of the human alphaMbeta2 headpiece fragment in complex with the nanobody (Nb) hCD11bNb1 at a resolution of 3.2 A. We show that the receptor headpiece adopts the closed conformation expected to exhibit low ligand affinity. The crystal structure indicates that in the R77H alphaM variant, associated with systemic lupus erythematosus, the modified allosteric relationship between ligand binding and integrin outside-inside signaling is due to subtle conformational effects transmitted over a distance of 40 A. Furthermore, we found the Nb binds to the alphaI domain of the alphaM subunit in an Mg(2+)-independent manner with low nanomolar affinity. Biochemical and biophysical experiments with purified proteins demonstrated that the Nb acts as a competitive inhibitor through steric hindrance exerted on the thioester domain of complement component iC3b attempting to bind the alphaM subunit. Surprisingly, we show that the Nb stimulates the interaction of cell-bound alphaMbeta2 with iC3b, suggesting that it may represent a novel high-affinity proteinaceous alphaMbeta2-specific agonist. Taken together, our data suggest that the iC3b-alphaMbeta2 complex may be more dynamic than predicted from the crystal structure of the core complex. We propose a model based on the conformational spectrum of the receptor to reconcile these observations regarding the functional consequences of hCD11bNb1 binding to alphaMbeta2. Structural insights into the function-modulating effects of nanobody binding to the integrin receptor alphaMbeta2.,Jensen RK, Pedersen H, Lorentzen J, Laursen NS, Vorup-Jensen T, Andersen GR J Biol Chem. 2022 Aug;298(8):102168. doi: 10.1016/j.jbc.2022.102168. Epub 2022, Jun 20. PMID:35738398 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Integrin 3D structures

spinqualitylabelsall models 7p2d, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image