6yw8

From Proteopedia

NMR solution structure of unbound recombinant human Nerve Growth Factor (rhNGF)

PDB ID 6yw8

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Structural highlights

6yw8 is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

The Nerve Growth Factor (NGF) neurotrophin acts in the maintenance and growth of neuronal populations. Despite the detailed knowledge of NGF's role in neuron physiology, the structural and mechanistic determinants of NGF bioactivity modulated by essential endogenous ligands are still lacking. We present the results of an integrated structural and advanced computational approach to characterize the extracellular ATP-NGF interaction. We mapped by NMR the interacting surface and ATP orientation on NGF and revealed the functional role of this interaction in the binding to TrkA and p75(NTR) receptors by SPR. The role of divalent ions was explored in conjunction with ATP. Our results pinpoint ATP as a likely transient molecular modulator of NGF signaling, in health and disease states.

Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions.,Paoletti F, Merzel F, Cassetta A, Ogris I, Covaceuszach S, Grdadolnik J, Lamba D, Golic Grdadolnik S Comput Struct Biotechnol J. 2021 May 7;19:2938-2949. doi:, 10.1016/j.csbj.2021.05.009. eCollection 2021. PMID:34136093^[4]

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

References

↑ 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
↑ 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
↑ 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
↑ Paoletti F, Merzel F, Cassetta A, Ogris I, Covaceuszach S, Grdadolnik J, Lamba D, Golic Grdadolnik S. Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions. Comput Struct Biotechnol J. 2021 May 7;19:2938-2949. doi:, 10.1016/j.csbj.2021.05.009. eCollection 2021. PMID:34136093 doi:http://dx.doi.org/10.1016/j.csbj.2021.05.009