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Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition.
Asor, Roi; Olerinyova, Anna; Burnap, Sean A; Kushwah, Manish S; Soltermann, Fabian; Rudden, Lucas S P; Hensen, Mario; Vasiljevic, Snezana; Brun, Juliane; Hill, Michelle; Chang, Liu; Dejnirattisai, Wanwisa; Supasa, Piyada; Mongkolsapaya, Juthathip; Zhou, Daming; Stuart, David I; Screaton, Gavin R; Degiacomi, Matteo T; Zitzmann, Nicole; Benesch, Justin L P; Struwe, Weston B; Kukura, Philipp.
Afiliación
  • Asor R; Physical and Theoretical Chemistry, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom.
  • Olerinyova A; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Burnap SA; Physical and Theoretical Chemistry, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom.
  • Kushwah MS; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Soltermann F; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Rudden LSP; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Hensen M; Physical and Theoretical Chemistry, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom.
  • Vasiljevic S; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Brun J; Physical and Theoretical Chemistry, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom.
  • Hill M; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Chang L; Department of Physics, Durham University, Durham DH1 3LE, United Kingdom.
  • Dejnirattisai W; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Supasa P; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Mongkolsapaya J; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Zhou D; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Stuart DI; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Screaton GR; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Degiacomi MT; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Zitzmann N; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
  • Benesch JLP; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom.
  • Struwe WB; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford OX3 7FZ, United Kingdom.
  • Kukura P; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom.
Proc Natl Acad Sci U S A ; 121(40): e2403260121, 2024 Oct.
Article en En | MEDLINE | ID: mdl-39298475
ABSTRACT
Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 11 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 11 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 11 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Unión Proteica / Multimerización de Proteína / Glicoproteína de la Espiga del Coronavirus / Enzima Convertidora de Angiotensina 2 / SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Unión Proteica / Multimerización de Proteína / Glicoproteína de la Espiga del Coronavirus / Enzima Convertidora de Angiotensina 2 / SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido