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6svl

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human Myeloid-derived growth factor (MYDGF) in complex with neutralizing Fab

Structural highlights

6svl is a 18 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.58Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MYDGF_HUMAN Bone marrow-derived monocyte and paracrine-acting protein that promotes cardiac myocyte survival and adaptive angiogenesis for cardiac protection and/or repair after myocardial infarction (MI). Stimulates endothelial cell proliferation through a MAPK1/3-, STAT3- and CCND1-mediated signaling pathway. Inhibits cardiac myocyte apoptosis in a PI3K/AKT-dependent signaling pathway (By similarity). Involved in endothelial cell proliferation and angiogenesis (PubMed:25581518).[UniProtKB:Q9CPT4]^[1]

Publication Abstract from PubMed

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.

Crystal structure and receptor-interacting residues of MYDGF - a protein mediating ischemic tissue repair.,Ebenhoch R, Akhdar A, Reboll MR, Korf-Klingebiel M, Gupta P, Armstrong J, Huang Y, Frego L, Rybina I, Miglietta J, Pekcec A, Wollert KC, Nar H Nat Commun. 2019 Nov 26;10(1):5379. doi: 10.1038/s41467-019-13343-7. PMID:31772377^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Korf-Klingebiel M, Reboll MR, Klede S, Brod T, Pich A, Polten F, Napp LC, Bauersachs J, Ganser A, Brinkmann E, Reimann I, Kempf T, Niessen HW, Mizrahi J, Schonfeld HJ, Iglesias A, Bobadilla M, Wang Y, Wollert KC. Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat Med. 2015 Feb;21(2):140-9. doi: 10.1038/nm.3778. Epub 2015 Jan 12. PMID:25581518 doi:http://dx.doi.org/10.1038/nm.3778
↑ Ebenhoch R, Akhdar A, Reboll MR, Korf-Klingebiel M, Gupta P, Armstrong J, Huang Y, Frego L, Rybina I, Miglietta J, Pekcec A, Wollert KC, Nar H. Crystal structure and receptor-interacting residues of MYDGF - a protein mediating ischemic tissue repair. Nat Commun. 2019 Nov 26;10(1):5379. doi: 10.1038/s41467-019-13343-7. PMID:31772377 doi:http://dx.doi.org/10.1038/s41467-019-13343-7