5HHD: Crystal Structure Of Chemically Synthesized Heterochiral {rfx037 Plus Vegf-a} Protein Complex In Space Group P21

Citation:
Abstract
Polypeptides composed entirely of d-amino acids and the achiral amino acid glycine (d-proteins) inherently have in vivo properties that are proposed to be near-optimal for a large molecule therapeutic agent. Specifically, d-proteins are resistant to degradation by proteases and are anticipated to be nonimmunogenic. Furthermore, d-proteins are manufactured chemically and can be engineered to have other desirable properties, such as improved stability, affinity, and pharmacokinetics. Thus, a well-designed d-protein therapeutic would likely have significant advantages over l-protein drugs. Toward the goal of developing d-protein therapeutics, we previously generated RFX001.D, a d-protein antagonist of natural vascular endothelial growth factor A (VEGF-A) that inhibited binding to its receptor. However, RFX001.D is unstable at physiological temperatures (Tm = 33 degrees C). Here, we describe RFX037.D, a variant of RFX001.D with extreme thermal stability (Tm > 95 degrees C), high affinity for VEGF-A (Kd = 6 nM), and improved receptor blocking. Comparison of the two enantiomeric forms of RFX037 revealed that the d-protein is more stable in mouse, monkey, and human plasma and has a longer half-life in vivo in mice. Significantly, RFX037.D was nonimmunogenic in mice, whereas the l-enantiomer generated a strong immune response. These results confirm the potential utility of synthetic d-proteins as alternatives to therapeutic antibodies.
PDB ID: 5HHDDownload
MMDB ID: 137334
PDB Deposition Date: 2016/1/10
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 5HHD: hexameric; determined by author and by software (PISA)
Molecular Components in 5HHD
Label Count Molecule
Proteins (2 molecules)
2
Vascular Endothelial Growth Factor a(Gene symbol: VEGFA)
Molecule annotation
Nucleotides(2 molecules)
2
D-peptide Rfx037.d
Molecule annotation
2
D-vascular Endothelial Growth Factor
Molecule annotation
Chemicals (5 molecules)
1
4
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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