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

被引：32

作者：

Ebenhoch, Rebecca ^{[1
]}

Akhdar, Abbas ^{[2
]}

Reboll, Marc R. ^{[2
]}

Korf-Klingebiel, Mortimer ^{[2
]}

Gupta, Priyanka ^{[3
]}

Armstrong, Julie ^{[3
]}

Huang, Yining ^{[3
]}

Frego, Lee ^{[3
]}

Rybina, Irina ^{[3
]}

Miglietta, John ^{[3
]}

Pekcec, Anton ^{[1
]}

Wollert, Kai C. ^{[2
]}

Nar, Herbert ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, D-88397 Biberach, Germany

[2] Hannover Med Sch, Div Mol & Translat Cardiol, Dept Cardiol & Angiol, Carl Neuberg Str 1, D-30625 Hannover, Germany

[3] Boehringer Ingelheim Pharmaceut Inc, 900 Ridgebury Rd, Ridgefield, CT 06877 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

COMPLEX; SIZE;

D O I：

10.1038/s41467-019-13343-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta-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.

引用

页数：10

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