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Binding and sensing diverse small molecules using shape-complementary pseudocycles.
An, Linna; Said, Meerit; Tran, Long; Majumder, Sagardip; Goreshnik, Inna; Lee, Gyu Rie; Juergens, David; Dauparas, Justas; Anishchenko, Ivan; Coventry, Brian; Bera, Asim K; Kang, Alex; Levine, Paul M; Alvarez, Valentina; Pillai, Arvind; Norn, Christoffer; Feldman, David; Zorine, Dmitri; Hicks, Derrick R; Li, Xinting; Sanchez, Mariana Garcia; Vafeados, Dionne K; Salveson, Patrick J; Vorobieva, Anastassia A; Baker, David.
Afiliação
  • An L; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Said M; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Tran L; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Majumder S; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Goreshnik I; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Lee GR; Department of Chemistry, University of Washington, Seattle, WA, USA.
  • Juergens D; Department of Chemical Engineering, University of Washington, Seattle, WA, USA.
  • Dauparas J; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Anishchenko I; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Coventry B; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Bera AK; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Kang A; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Levine PM; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Alvarez V; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Pillai A; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Norn C; Graduate Program in Molecular Engineering, University of Washington, Seattle, WA, USA.
  • Feldman D; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Zorine D; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Hicks DR; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Li X; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Sanchez MG; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Vafeados DK; Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Salveson PJ; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
  • Vorobieva AA; Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Baker D; Institute for Protein Design, University of Washington, Seattle, WA, USA.
Science ; 385(6706): 276-282, 2024 Jul 19.
Article em En | MEDLINE | ID: mdl-39024436
ABSTRACT
We describe an approach for designing high-affinity small molecule-binding proteins poised for downstream sensing. We use deep learning-generated pseudocycles with repeating structural units surrounding central binding pockets with widely varying shapes that depend on the geometry and number of the repeat units. We dock small molecules of interest into the most shape complementary of these pseudocycles, design the interaction surfaces for high binding affinity, and experimentally screen to identify designs with the highest affinity. We obtain binders to four diverse molecules, including the polar and flexible methotrexate and thyroxine. Taking advantage of the modular repeat structure and central binding pockets, we construct chemically induced dimerization systems and low-noise nanopore sensors by splitting designs into domains that reassemble upon ligand addition.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ligação Proteica / Proteínas / Bibliotecas de Moléculas Pequenas / Aprendizado Profundo Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ligação Proteica / Proteínas / Bibliotecas de Moléculas Pequenas / Aprendizado Profundo Idioma: En Ano de publicação: 2024 Tipo de documento: Article