1NT3

HUMAN NEUROTROPHIN-3

Summary for 1NT3

• Entry DOI: 10.2210/pdb1nt3/pdb
• Descriptor: PROTEIN (NEUROTROPHIN-3) (2 entities in total)
• Functional Keywords: neurotrophin, growth factor, cystine knot, hormone-growth factor-neuropeptide complex, hormone/growth factor/neuropeptide
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P20783
• Total number of polymer chains: 1
• Total formula weight: 13649.40

Authors

Butte, M.J.,Hwang, P.K.,Mobley, W.C.,Fletterick, R.J. (deposition date: 1999-05-17, release date: 1999-06-06, Last modification date: 2024-11-20)

Primary citation

Butte, M.J.,Hwang, P.K.,Mobley, W.C.,Fletterick, R.J.
Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors.
Biochemistry, 37:16846-16852, 1998

PubMed Abstract: Neurotrophin-3 (NT-3) is a cystine knot growth factor that promotes the survival, proliferation, and differentiation of developing neurons and is a potential therapeutic for neurodegenerative diseases. To clarify the structural basis of receptor specificity and the role of neurotrophin dimerization in receptor activation, the structure of the NT-3 homodimer was determined using X-ray crystallography. The orthorhombic crystals diffract to 2.4 A, with dimer symmetry occurring about a crystallographic 2-fold axis. The overall structure of NT-3 resembles that of the other neurotrophins, NGF and BDNF; each protomer forms a twisted four-stranded beta sheet, with three intertwined disulfide bonds. There are notable differences, however, between NT-3 and NGF in the surface loops and in three functionally important regions, shown in previous mutagenesis studies to be critical for binding. One such difference implies that NT-3's binding affinity and specificity depend on a novel hydrogen bond between Gln 83, a residue important for binding specificity with TrkC, and Arg 103, a residue crucial for binding affinity with TrkC. NT-3's extensive dimer interface buries much of the otherwise solvent-accessible hydrophobic surface area and suggests that the dimeric state is stabilized through the formation of this hydrophobic core. A comparison of the dimer interface between the NT-3 homodimer and the BDNF/NT-3 heterodimer reveals similar patterns of hydrogen bonds and nonpolar contacts, which reinforces the notion that the evolutionarily conserved neurotrophin interface resulted from the need for receptor dimerization in signal initiation.

PubMed: 9836577
DOI: 10.1021/bi981254o

Experimental method

X-RAY DIFFRACTION (2.4 Å)