5f8y | pdb_00005f8y
Crystal structure of a Crenomytilus grayanus lectin in complex with galactosamine
Structural highlights
FunctionLEC_CREGR Galactose-binding lectin (PubMed:23886951, PubMed:27010847, PubMed:9568372, PubMed:28636877). Binds both alpha and beta anomer of galactose (Gal), but has a stronger interaction with the glycans having alpha Gal at the non-reducing end and binds beta Gal weakly only in highly branched glycans. Has high affinity to Galalpha1-4Galbeta1-4GlcNAc (PubMed:28636877). Binds N-acetyl-2-deoxy-2-amino-galactose (2-deoxy-GalNAc) (PubMed:23886951, PubMed:9568372). Binds N-acetylgalactosamine (GalNAc) (PubMed:26439416). Binds porcine stomach mucin (PSM) with high affinity (PubMed:26439416, PubMed:30486373). Binds galactosamine (PubMed:27010847). Binds laminin, bovine submaxillary mucin (BSM), fibronectin, type I collagen and gelatin with a decreasing affinity, respectively (Ref.3). Has hemagglutinating activity towards human type A erythrocytes (PubMed:9568372, PubMed:26439416, Ref.3). Hemagglutinates also human type 0, B and AB erythrocytes as well as rabbit and mouse erythrocytes (PubMed:9568372). Agglutinates both Gram-positive and Gram-negative bacteria including B.subtilis ATCC 6633, S.aureus ATCC 21027 and E.coli 3254, respectively. No agglutination activity towards Gram-positive S.amurskyense CMM 3673. Has bacteriostatic activity on S.amurskyense CMM 3673, B.subtilis ATCC 6633, S.aureus ATCC 21027 and E.coli 3254. However, has no agglutination nor bacteriostatic activity on Gram-negative C.scophthalmum CIP 104199 or A.troitsensis KMM 3674 (PubMed:23886951). Inhibits growth of fungi from the genera Aspergillus, Penicillium, Trichoderma and st. Mycelia. Inhibits germination of spores and hyphal growth of them (PubMed:25482060). Has dose-dependent cytotoxic effect on the human globotriaosylceramide (Gb3)-expressing Burkitt's lymphoma (Raji) cell line. Binds to Gb3 in these cells leading to activation of caspase-9/3 and PARP (PubMed:28636877). Has dose-dependent cytotoxic effect on the Gb3-expressing human MCF-7 breast cancer cell line (PubMed:27010847). No cytotoxic effect on myelogenous leukemia K562 cell line, which does not express Gb3 (PubMed:28636877). Activates immune responses in mice and increases cytokine production of TNF-alpha, IL-6 and MCP-1 in the serum and the peritoneal lavage of mice. Induces TNF-alpha and IL-6 secretion in mouse RAW264.7 macrophages, mouse bone marrow-derived macrophages, human THP-1 macrophages, human peripheral blood mononuclear cells (PBMCs) and human blood monocyte-derived macrophages. TNF-alpha production in macrophages could not be inhibited by GalNAc, GalN or Gal, indicating that induced cytokine production is separate from its sugar binding activity. Increases intracellular reactive oxygen species levels, expression and phosphorylation of protein kinases PKC alpha/delta, expression of COX-2 and NF-kappaB, and activates the MAPK pathway by increasing the phosphorylation of ERK1/2, JNK1/2 and p38 in mouse RAW264.7 macrophages. Induces endotoxin tolerance in lipopolysaccharide(LPS)-activated macrophages by down-regulating IRAK2 expression, reducing JNK1/2 phosphorylation and NF-kappaB activation. Can slightly increase the bactericidal activity of RAW264.7 macrophages (PubMed:28740170). Has DNA-binding activity (PubMed:27010847). Recognizes pathogen-associated molecular patterns (PAMPs) and binds to LPS from E.coli, but has only little binding to beta-1,3-glucan from E.gracilis and peptidoglycan from S.aureus. Activates secretion of TNF-alpha and IFN-gamma by the human peripheral blood cells (HPBCs) (PubMed:31905927). May be involved in innate immunity acting as an antibacterial and antifungal agent involved in the recognition and clearance of pathogens (PubMed:23886951, PubMed:25482060, PubMed:31905927).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedIn this study, we report the structure and function of a lectin from the sea mollusk Crenomytilus grayanus collected from the sublittoral zone of Peter the Great Bay of the Sea of Japan. The crystal structure of C. grayanus lectin (CGL) was solved to a resolution of 1.08 A, revealing a beta-trefoil fold that dimerizes into a dumbbell-shaped quaternary structure. Analysis of the crystal CGL structures bound to galactose, galactosamine, and globotriose Gb3 indicated that each CGL can bind three ligands through a carbohydrate-binding motif involving an extensive histidine- and water-mediated hydrogen bond network. CGL binding to Gb3 is further enhanced by additional side-chain-mediated hydrogen bonds in each of the three ligand-binding sites. NMR titrations revealed that the three binding sites have distinct microscopic affinities toward galactose and galactosamine. Cell viability assays showed that CGL recognizes Gb3 on the surface of breast cancer cells, leading to cell death. Our findings suggest the use of this lectin in cancer diagnosis and treatment. A Multivalent Marine Lectin from Crenomytilus grayanus Possesses Anti-cancer Activity through Recognizing Globotriose Gb3.,Liao JH, Chien CT, Wu HY, Huang KF, Wang I, Ho MR, Tu IF, Lee IM, Li W, Shih YL, Wu CY, Lukyanov PA, Hsu ST, Wu SH J Am Chem Soc. 2016 Apr 13;138(14):4787-95. doi: 10.1021/jacs.6b00111. Epub 2016 , Apr 1. PMID:27010847[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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