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

Autor:	Ebenhoch R; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Akhdar A; Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany., Reboll MR; Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany., Korf-Klingebiel M; Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany., Gupta P; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Armstrong J; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Huang Y; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Frego L; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Rybina I; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Miglietta J; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Pekcec A; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Wollert KC; Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany., Nar H; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. herbert.nar@boehringer-ingelheim.com.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Nov 26; Vol. 10 (1), pp. 5379. Date of Electronic Publication: 2019 Nov 26.
DOI:	10.1038/s41467-019-13343-7
Abstrakt:	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.
Databáze:	MEDLINE
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