ArticleJournal of immunology (Baltimore, Md. : 1950)2011
Stable coordination of the inhibitory Ca2+ ion at the metal ion-dependent adhesion site in integrin CD11b/CD18 by an antibody-derived ligand aspartate: implications for integrin regulation and structure-based drug design.
Article in Journal of immunology (Baltimore, Md. : 1950), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. 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, 32 citations in OpenAlex.
- The Integrin Receptors: From Discovery to Structure to Medicines.Immunological reviews · 2025Review
- Structural biology of complement receptors.Frontiers in immunology · 2023Review
- INTEGRINS: A BEDSIDE TO BENCH TO BEDSIDE STORY.Transactions of the American Clinical and Climatological Association · 2023Article
- Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2.Cell reports · 2022Article
- CD11b agonists offer a novel approach for treating lupus nephritis.Translational research : the journal of laboratory and clinical medicine · 2022Review
- A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction.Basic research in cardiology · 2021Article
- β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration.Frontiers in immunology · 2021Review
- Roles of Membrane Domains in Integrin-Mediated Cell Adhesion.International journal of molecular sciences · 2020Review
- Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement.Cell reports · 2020Article
- Molecular mechanism of leukocidin GH-integrin CD11b/CD18 recognition and species specificity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural basis of the leukocyte integrin Mac-1 I-domain interactions with the platelet glycoprotein Ib.Blood advances · 2019Article
- A three-way inter-molecular network accounts for the CaThe Journal of biological chemistry · 2018Article
- Salt-bridge modulates differential calcium-mediated ligand binding to integrin α1- and α2-I domains.Scientific reports · 2018Article
- Structural Immunology of Complement Receptors 3 and 4.Frontiers in immunology · 2018Review
- Integrins as Therapeutic Targets: Successes and Cancers.Cancers · 2017Review
- Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys.Nature communications · 2017Article
- Biology and structure of leukocyte βF1000Research · 2016Review
- Article
- Agonist leukadherin-1 increases CD11b/CD18-dependent adhesion via membrane tethers.Biophysical journal · 2013Article
- Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury.Biochimica et biophysica acta · 2013Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg(2+) ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca(2+) ion over the Mg(2+) ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca(2+) ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca(2+) ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca(2+) ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.
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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.