3D Structure of Eryththropoietin

CPK Color Scheme
C O N P S


Erytropoietin is a glycoprotein that is critical for erythrocyte, or red blood cell production. To learn more about erythropoietin's role in red blood cell production, as well as diseases that can occur if mutations develop in erythropoietin click here.



Some Of the Major Structural features of Erythropoietin are:

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Erythrpoietin is made up of a four-membered alpha-helical bundle with connecting loops. Alpha- Helices are labeled A through D in order from the N- terminus to the C-terminus.Helix A is shown here in blue, a small minor helix B' shown in turqoise, Helix B in turquiose/green, Heix C in green/yellow, minor helix C' shown in yellow and Helix D in orange/red. Note: these helices are not shown in CPK colors.
To highlight alpha helix A, click here.
Mini-Helix B', click here.
Helix B,click here.
Helix C, click here.
Mini- Helix C', click here. Zoom in, click here.
Helix D, click here. Note: when highlighting helices, helices turn yellow.

Four cysteinyl residues form 2 intrachain disulfide bridges, one from Cys7 to Cys 161 and another from Cys 29 to Cys 33. The disulfide bridge from Cys 7 to Cys 161 acts to hold together Alpha helices A and D. Click to see in relation to helices. zoom in

Receptor Binding Sites. Erythropoietin binds to two EPO receptors, and thus contains two binding sites. The high affinity binding site, or site 1, includes residues Thr 41- Lys 52, Asn 147, Arg 150, and Gly 151. Here, the surface residues are shown.

The low- affinity receptor binding site, or site 2, includes residues Val 11, Arg 14, Tyr 15, Ser 100, Arg 103, Ser 104, and Leu 108. These residues all lie within the AC helical bundle. Zoom in on low- affinity binding site. Click here.

The aromatic amino acids Phe 142, Tyr 145, Phe 148 and Tyr 156 form the hydrophobic core of EPO. These amino acids are located along the interior side of the D- helix and are located against the hydropohobic side chains of the A,B, and C helices. These hydrophobic core residues are found to be similar within many species. It is not surprising that any mutation of one of these core residues greatly impacts protein folding.
For a view of the hydrophobic core from a different angle, click here.

Inside the core of Erythropoietin, an important amino acid in maintaining the structure of the protein is the amino acid Glyccine 151. At Glyccine 151, there is a kink in the D helix. This kink serves to bring the sidechain that contains Lys 152 into position so that it interacts hydrophobically with Val 63, Trp 51, and Phe 148. When either Gys 151 or Lys 152 are replaced by Ala, a large loss of bioactivity results.
References


Cheetham JC, Smith DM, Aoki NH. 1998. NMR structure of human erythropoietin and a comparision with its receptor bound conformation. Nature Structural Biology 5(10): 861-866.

Kogoy John. CPK Color Scheme. 2003. Permission to use granted.

Protein Data Bank. 2003. 1BUY: Human Erythropoietin, NMR Minimized Average Structure.

Syed RS, Reid SW, Li C, Cheetham JC, Aoki KH, Liu B, Zhan H, Osslund TD, Chirino AJ, Zhang J, Finer- Moore J, Elliott S, Sitney K, Katz BA, Matthews DJ, Wendoloski JJ, Egrie J, Stroud, RM. 1998. Effieciency of Signalling through cytokine receptors depends critically on receptor orientation. Nature 395: 511-516.