ArticleProceedings of the National Academy of Sciences of the United States of America2009
The crystal structure of sphingosine-1-phosphate in complex with a Fab fragment reveals metal bridging of an antibody and its antigen.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 22 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 53 citations in OpenAlex.
- Targeting Sphingosine 1-Phosphate Metabolism as a Therapeutic Avenue for Prostate Cancer.Cancers · 2023Review
- High-resolution structural analysis of enterovirus-reactive polyclonal antibodies in complex with whole virions.PNAS nexus · 2022Article
- Antigen binding by conformational selection in near-germline antibodies.The Journal of biological chemistry · 2022Article
- Antibody structure prediction using interpretable deep learning.Patterns (New York, N.Y.) · 2022Article
- Ion Binding Properties of a Naturally Occurring Metalloantibody.Antibodies (Basel, Switzerland) · 2020Article
- Breaking the law: unconventional strategies for antibody diversification.Nature reviews. Immunology · 2019Review
- High-affinity pan-specific monoclonal antibodies that target cysteinyl leukotrienes and show efficacy in an acute model of colitis.Journal of lipid research · 2017Article
- A novel approach for measuring sphingosine-1-phosphate and lysophosphatidic acid binding to carrier proteins using monoclonal antibodies and the Kinetic Exclusion Assay.Journal of lipid research · 2016Article
- Sphingolipid transfer proteins defined by the GLTP-fold.Quarterly reviews of biophysics · 2015Article
- A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas.Frontiers in oncology · 2015Review
- Amphiphilic degradable polymers for immobilization and sustained delivery of sphingosine 1-phosphate.Acta biomaterialia · 2014Article
- GPCR ontology: development and application of a G protein-coupled receptor pharmacology knowledge framework.Bioinformatics (Oxford, England) · 2013Article
- Regulation of the Hippo pathway and implications for anticancer drug development.Trends in pharmacological sciences · 2013Review
- The Hippo pathway and human cancer.Nature reviews. Cancer · 2013Review
- Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis.EMBO molecular medicine · 2012Article
- Regulation of metabolism and transport of sphingosine-1-phosphate in mammalian cells.Molecular and cellular biochemistry · 2012Review
- The role of sphingosine 1-phosphate in immunity and sepsis.American journal of clinical and experimental immunology · 2012Article
- Biochemical and structural characterization of lysophosphatidic Acid binding by a humanized monoclonal antibody.Journal of molecular biology · 2011Article
- Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration.British journal of pharmacology · 2011Review
- Review
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The pleiotropic signaling lipid sphingosine-1-phosphate (S1P) plays significant roles in angiogenesis, heart disease, and cancer. LT1009 (also known as sonepcizumab) is a humanized monoclonal antibody that binds S1P with high affinity and specificity. Because the antibody is currently in clinical trials, it is important to confirm by structural and biochemical analyses that it binds its target in a predictable manner. Therefore, we determined the structure of a complex between the LT1009 antibody Fab fragment and S1P refined to 1.90 A resolution. The antibody employs unique and diverse strategies to recognize its antigen. Two metal ions bridge complementarity determining regions from the antibody light chain and S1P. The coordination geometry, inductively coupled plasma spectroscopy, surface plasmon resonance spectroscopy, and biochemical assays suggest that these are Ca(2+). The amino alcohol head group of the sphingosine backbone is recognized through hydrogen bonding interactions from 1 aa side chain and polypeptide backbone atoms of the antibody light and heavy chains. The S1P hydrophobic tail is almost completely enclosed within a hydrophobic channel formed primarily by the heavy chain. Both treatment of the complex with metal chelators and mutation of amino acids in the light chain that coordinate the metal atoms or directly contact the polar head group abrogate binding, while mutations within the hydrophobic cavity also decrease S1P binding affinity. The structure suggests mechanistic details for recognition of a signaling lipid by a therapeutic antibody candidate. Moreover, this study provides direct structural evidence that antibodies are capable of using metals to bridge antigen:antibody complexes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.