Crystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair

Rebecca Ebenhoch, Abbas Akhdar, Marc R. Reboll, Mortimer Korf-Klingebiel, Priyanka Gupta, Julie Armstrong, Yining Huang, Lee Frego, Irina Rybina, John Miglietta, Anton Pekcec, Kai C. Wollert and Herbert Nar ()
Additional contact information
Rebecca Ebenhoch: Boehringer Ingelheim Pharma GmbH & Co. KG
Abbas Akhdar: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School
Marc R. Reboll: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School
Mortimer Korf-Klingebiel: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School
Priyanka Gupta: Boehringer Ingelheim Pharmaceuticals, Inc.
Julie Armstrong: Boehringer Ingelheim Pharmaceuticals, Inc.
Yining Huang: Boehringer Ingelheim Pharmaceuticals, Inc.
Lee Frego: Boehringer Ingelheim Pharmaceuticals, Inc.
Irina Rybina: Boehringer Ingelheim Pharmaceuticals, Inc.
John Miglietta: Boehringer Ingelheim Pharmaceuticals, Inc.
Anton Pekcec: Boehringer Ingelheim Pharma GmbH & Co. KG
Kai C. Wollert: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School
Herbert Nar: Boehringer Ingelheim Pharma GmbH & Co. KG

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Myeloid-derived growth factor (MYDGF) is a paracrine-acting protein that is produced by bone marrow-derived monocytes and macrophages to protect and repair the heart after myocardial infarction (MI). This effect can be used for the development of protein-based therapies for ischemic tissue repair, also beyond the sole application in heart tissue. Here, we report the X-ray structure of MYDGF and identify its functionally relevant receptor binding epitope. MYDGF consists of a 10-stranded β-sandwich with a folding topology showing no similarities to other cytokines or growth factors. By characterizing the epitope of a neutralizing antibody and utilizing functional assays to study the activity of surface patch-mutations, we were able to localize the receptor interaction interface to a region around two surface tyrosine residues 71 and 73 and an adjacent prominent loop structure of residues 97–101. These findings enable structure-guided protein engineering to develop modified MYDGF variants with potentially improved properties for clinical use.

Date: 2019
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DOI: 10.1038/s41467-019-13343-7

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