5jz7

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NGF IN COMPLEX WITH MEDI578 scFv

Structural highlights

5jz7 is a 12 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 3.4Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NGF_HUMAN Defects in NGF are the cause of hereditary sensory and autonomic neuropathy type 5 (HSAN5) [MIM:608654. The hereditary sensory and autonomic neuropathies are a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable.[1] [2] [3]

Function

NGF_HUMAN Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades through those receptor tyrosine kinase to regulate neuronal proliferation, differentiation and survival.

Publication Abstract from PubMed

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins.

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.,Dobson CL, Devine PW, Phillips JJ, Higazi DR, Lloyd C, Popovic B, Arnold J, Buchanan A, Lewis A, Goodman J, van der Walle CF, Thornton P, Vinall L, Lowne D, Aagaard A, Olsson LL, Ridderstad Wollberg A, Welsh F, Karamanos TK, Pashley CL, Iadanza MG, Ranson NA, Ashcroft AE, Kippen AD, Vaughan TJ, Radford SE, Lowe DC Sci Rep. 2016 Dec 20;6:38644. doi: 10.1038/srep38644. PMID:27995962[4]

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

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Citations
22 reviews cite this structure
Phage Display Derived Monoclonal Antibodies: From Bench to Bedside.
Alfaleh et al. (2020)
21 more
36 other articles
No citations found

See Also

References

  1. ↑ Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004 Apr 15;13(8):799-805. Epub 2004 Feb 19. PMID:14976160 doi:10.1093/hmg/ddh096
  2. ↑ Carvalho OP, Thornton GK, Hertecant J, Houlden H, Nicholas AK, Cox JJ, Rielly M, Al-Gazali L, Woods CG. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J Med Genet. 2011 Feb;48(2):131-5. doi: 10.1136/jmg.2010.081455. Epub 2010 Oct, 26. PMID:20978020 doi:10.1136/jmg.2010.081455
  3. ↑ Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID:22302274 doi:10.1007/s00415-011-6397-y
  4. ↑ Dobson CL, Devine PW, Phillips JJ, Higazi DR, Lloyd C, Popovic B, Arnold J, Buchanan A, Lewis A, Goodman J, van der Walle CF, Thornton P, Vinall L, Lowne D, Aagaard A, Olsson LL, Ridderstad Wollberg A, Welsh F, Karamanos TK, Pashley CL, Iadanza MG, Ranson NA, Ashcroft AE, Kippen AD, Vaughan TJ, Radford SE, Lowe DC. Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo. Sci Rep. 2016 Dec 20;6:38644. doi: 10.1038/srep38644. PMID:27995962 doi:http://dx.doi.org/10.1038/srep38644

Contents


PDB ID 5jz7

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