Mutation of tryptophan-21 in mouse nerve growth factor (NGF) affects binding to the fast NGF receptor but not induction of neurites on PC12 cells

doi:10.1098/rspb.1991.0159

Cited by 24 publications

(11 citation statements)

References 33 publications

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“…Having placed biochemical and mutagenesis data for NGF in structural context by analogy with the receptor binding surface of TNF-@, we have shown that the model of NTR fits into the presumptive Color coding of NTR domains is the same as in Figure 2, except that linker residues are not separately colored. binding site on NGF (Rosenberg et al, 1986;Ibaiiez et al, 1990Ibaiiez et al, , 1991Ibaiiez et al, , 1992Ibaiiez et al, , 1993; Drinkwater et al, 1991Drinkwater et al, , 1993 Banner et al, 1993). This complex is formed in a stereospecific way, with docking scores that are more than 75% of the regenerated TNF/TNFR crystal complex.…”

Section: Insights From Molecular Modeling and Dockingmentioning

confidence: 99%

“…A likely binding site for NTR was identified on NGF using a list of residues generated from binding analyses of NGF derivatives and mutants (Rosenberg et al, 1986;Ibaiiez et al, 1990Ibaiiez et al, , 1992Drinkwater et al, 1991Drinkwater et al, , 1993. Known contact residues were then distributed along a dimer interface of the NGF crystal structure on the assumption that receptors of a family might have similar modes of ligand binding.…”

Section: Analysis Of Receptor-ligand Interactions By Molecular Dockingmentioning

confidence: 99%

“…The N-terminal loop of subdomain 111 appeared to interact with residues near the N-and C-termini of NGF, including Gly 10, Ser 113, and Arg 114 (Drinkwater et al, 1993). In all, more than half of the NGF residues at the modeled NTR/NGF interface have been implicated by biochemistry and mutagenesis (Rosenberg et al, 1986;Ibaiiez et al, 1990Ibaiiez et al, , 1992Drinkwater et al, 1991Drinkwater et al, , 1993.…”

Section: Analysis Of Receptor-ligand Interactions By Molecular Dockingmentioning

confidence: 99%

“…The crystal structure of a TNF-/3 trimer in complex with its receptor revealed that TNFR subunits bind in the interface between ligand subunits (Banner et al, 1993). An analogous receptor-binding site on NGF was evaluated using data from mutagenesis and biochemical modification (Rosenberg et al, 1986;lbaiiez et al, 1990, 1991Drinkwater et al, 1991Drinkwater et al, , 1993. Several potential binding surfaces were explored on the receptor model by docking into the crystal structure of NGF (Shoichet & Kuntz, 1991;Meng et al, 1992).…”

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confidence: 99%

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Modeled structure of the 75-kDa neurotrophin receptor

Chapman

Kuntz

1995

Protein Sci.

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Motifs in ligand-binding domains of the neurotrophin (NTR) and lymphotoxin (TNFR-I) receptors define a family of receptors that mediates programmed cell death. We have explored relationships of architecture and function in this family through a molecular model of NTR, also called p75NGFR or LANR. Modeling by homology took advantage of four modular subdomains in the crystal structure of TNFR-I that also occur in NTR. Hypothetical complexes between the model and a ligand structure (for nerve growth factor, NGF) were then examined using docking software. NTR appears to bind in the dimer interface of NGF, making two sets of contacts. NTR subdomains 111 and IV provide the ligand-contact surfaces, in contrast to TNFR, in which subdomains 11 and III contact TNF-6. NTR subdomain I1 appears to have been evolutionarily modified, potentially contributing to an interface between receptor subunits. These and other specific predictions of the model will require experimental confirmation.

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Section: Insights From Molecular Modeling and Dockingmentioning

confidence: 99%

Section: Analysis Of Receptor-ligand Interactions By Molecular Dockingmentioning

confidence: 99%

Section: Analysis Of Receptor-ligand Interactions By Molecular Dockingmentioning

confidence: 99%

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confidence: 99%

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Modeled structure of the 75-kDa neurotrophin receptor

Chapman

Kuntz

1995

Protein Sci.

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“…A derivative, in which 0.9 tryptophans had been oxidized, had only 1.2% the affinity of the native molecule and a derivative with 2 oxindole residues did not compete with native NGF for receptor binding at all. Drinkwater et al (1991) also reexamined this question using site-directed mutagenesis, substituting phenylalanine, leucine, and serine for Trp 21 (W21F, W21L, and W21S). W21S was produced at levels that were below detection, but both W21F and W21L were obtained in sufficient quantities for further testing.…”

Section: Tryptophanmentioning

confidence: 99%

Nerve growth factor: Structure/function relationships

et al. 1994

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Nerve growth factor (NGF), which has a tertiary structure based on a cluster of 3 cystine disulfides and 2 very extended, but distorted 0-hairpins, is the prototype of a larger family of neurotrophins. Prior to the availability of cloning techniques, the mouse submandibular gland was the richest source of NGF and provided sufficient material to enable its biochemical characterization. It binds as a dimer to at least 2 cell-surface receptor types expressed in a variety of neuronal and non-neuronal cells. Residues involved in these interactions and in the maintenance of tertiary and quaternary structure have been identified by chemical modification and site-directed mutagenesis, and this information can be related to their location in the 3-dimensional structure. For example, interactions between aromatic residues contribute to the stability of the NGF dimer, and specific surface lysine residues participate in receptor contacts. The conclusion from these studies is that receptor interactions involve broad surface regions, which may be composed of residues from both protomers in the dimer.Keywords: nerve growth factor; neurotrophins; structure/function relationships The elucidation of the structure/function relationships of a protein requires a precise knowledge of the 3-dimensional structure and the identification of the residues that participate in biological activity. The latter were traditionally defined by chemical modification, which has now been supplanted, to a large degree, by site-directed mutagenesis, primarily because it offers the possibility of making substitutions anywhere in the molecule. However, despite its limitations, chemical modification does offer 1 major advantage: it is carried out on the intact protein and does not generally require refolding, a problem that has hampered the preparation of many recombinant derivatives. As is often the case, both approaches used in concert may provide much more information than either alone.

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Specificity of neurotrophin-3 determined by loss-of-function mutagenesis

Kullander¹,

Kylberg²,

Ebendal³

1997

J. Neurosci. Res.

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Neurotrophin-3 (NT-3) is a member of the family of neurotrophic factors, which also includes nerve growth factor (NGF) and which have specific activities on different subsets of vertebrate neurons. The aim of this study was to determine which residues in NT-3 direct its specificity to the cognate TrkC receptor. It was possible to replace 80% of the residues in NT-3 with NGF residues without loss of specific activity. Residues D72, Y85, R87, W101, S107, and A111, together with either the residues F12, V18, V20, M37, V42, F54, and K57 or the variable regions IV and V, accounted for the specificity of NT-3. It is concluded that NGF and NT-3 use overlapping as well as separated regions for determination of specificities for their cognate receptors TrkA and TrkC, respectively.

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Mutation of tryptophan-21 in mouse nerve growth factor (NGF) affects binding to the fast NGF receptor but not induction of neurites on PC12 cells

Cited by 24 publications

References 33 publications

Modeled structure of the 75-kDa neurotrophin receptor

Modeled structure of the 75-kDa neurotrophin receptor

Nerve growth factor: Structure/function relationships

Specificity of neurotrophin-3 determined by loss-of-function mutagenesis

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