National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM147414
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM092802
United States
The Pew Charitable Trusts
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM008268-33
United States
Howard Hughes Medical Institute (HHMI)
United States
Citation
Journal: Nat Commun / Year: 2023 Title: De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / ...Authors: Anindya Roy / Lei Shi / Ashley Chang / Xianchi Dong / Andres Fernandez / John C Kraft / Jing Li / Viet Q Le / Rebecca Viazzo Winegar / Gerald Maxwell Cherf / Dean Slocum / P Daniel Poulson / Garrett E Casper / Mary L Vallecillo-Zúniga / Jonard Corpuz Valdoz / Marcos C Miranda / Hua Bai / Yakov Kipnis / Audrey Olshefsky / Tanu Priya / Lauren Carter / Rashmi Ravichandran / Cameron M Chow / Max R Johnson / Suna Cheng / McKaela Smith / Catherine Overed-Sayer / Donna K Finch / David Lowe / Asim K Bera / Gustavo Matute-Bello / Timothy P Birkland / Frank DiMaio / Ganesh Raghu / Jennifer R Cochran / Lance J Stewart / Melody G Campbell / Pam M Van Ry / Timothy Springer / David Baker / Abstract: The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between ...The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
Entire : Ternary complex of integrin heterodimer (alpha-v beta-8) and the ...
Entire
Name: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
Components
Complex: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf
Protein or peptide: Integrin alpha-V heavy chain
Protein or peptide: Integrin beta-8
Protein or peptide: Minibinder B8_BP_dslf
Ligand: CALCIUM ION
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Ligand: MAGNESIUM ION
-
Supramolecule #1: Ternary complex of integrin heterodimer (alpha-v beta-8) and the ...
Supramolecule
Name: Ternary complex of integrin heterodimer (alpha-v beta-8) and the de novo minibinder protein B8_BP_dslf type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 Details: Integrin expressed in expiCHO cells, minibinder expressed in e. coli
Source (natural)
Organism: Homo sapiens (human)
-
Macromolecule #1: Integrin alpha-V heavy chain
Macromolecule
Name: Integrin alpha-V heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
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