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Structure paper

TitleDe novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5660, Year 2023
Publish dateSep 13, 2023
AuthorsAnindya 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 /
PubMed AbstractThe 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.
External linksNat Commun / PubMed:37704610 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.8 - 3.4 Å
Structure data

41153

8tcf

EMDB-41153, PDB-8tcf:
Integrin alpha-v beta-8 in complex with minibinder B8_BP_dsulf
Method: EM (single particle) / Resolution: 2.9 Å

41154

8tcg

EMDB-41154, PDB-8tcg:
Integrin alpha-v beta-6 in complex with minibinder B6_BP_dslf
Method: EM (single particle) / Resolution: 3.4 Å

PDB-7lmv:
SPECIFIC INHIBITOR OF INTEGRIN ALPHA-V BETA-6
Method: X-RAY DIFFRACTION / Resolution: 1.9 Å

PDB-7lmx:
A HIGHLY SPECIFIC INHIBITOR OF INTEGRIN ALPHA-V BETA-6 WITH A DISULFIDE
Method: X-RAY DIFFRACTION / Resolution: 1.8 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-MG:
Unknown entry

ChemComp-MN:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDE NOVO PROTEIN / de novo design / inhibitor / integrin / fibrosis / Complex / heterodimer / signaling / TGF-Beta / ECM-binding

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