Theoretical and Biochemical Studies on the Selectivity of Nerve Growth Factor for Transition Metal Cations
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- 作者：Igor L. Shamovsky ; Gregory M. Ross ; Richard J. Riopelle ; and Donald F. Weaver
- 刊名：Journal of the American Chemical Society
- 出版年：1999
- 出版时间：October 27, 1999
- 年：1999
- 卷：121
- 期：42
- 页码：9797 - 9806
- 全文大小：438K
- 年卷期：v.121,no.42(October 27, 1999)
- ISSN：1520-5126
文摘
Selective effects of transition metal cations (Mn+) on biological activities of nerve growth factor(NGF) have recently been described. It has been suggested that four residues in NGF (His4, His8, His84', andAsp105') form a distorted square base pyramidal coordination complex [M(N·His)3(-O2C
fchars/gamma.gif" BORDER=0 >·Asp)], thereby inducinga conformational transition within the NGF amino terminus (residues Ser1-Phe12), which constitutes a criticalpart of the receptor binding determinant. In this report, we provide theoretical and experimental data validatingthis structure and suggest a model for the selectivity of the M(II)-NGF interaction. The structures of themodel complexes [M(NH3)3(-O2CCH3)] and [M(HNCH2)3(-O2CCH3)] (mimicking the M(II)-NGF coordinationsite) with first- and second-row divalent transition metal cations Co(II), Ni(II), Cu(II), Zn(II), Rh(II), Pd(II),and Cd(II) were studied by fully optimized ab initio molecular orbital calculations. Regardless of the chemicalnature of the neutral ligands, these cations split into three groups: (i) Ni(II), Cu(II), and Pd(II) (d8 and d9metals), which prefer a square pyramidal coordination; (ii) Co(II), Rh(II) (d7 metals), and Zn(II) (the d10 first-row transition metal), which prefer a triangular bipyramidal environment; and (iii) Cd(II) (the d10 second-rowtransition metal), which has no intrinsic stereochemical preference. It should be noted, however, thatstereochemical preferences of Cu(II) and Zn(II) are minor. Molecular mechanics calculations demonstrate thatparticular geometric features of the M(II)-NGF coordination site are most suitable for metal cations ofintermediate sizes. Taken together with the intrinsic stereochemical preference of transition metal cations,three ions (Zn(II), Cu(II) and Pd(II)) are expected to be specific NGF antagonists, which is consistent with theeffects of these ions on the conformation and biological activities of NGF.
fchars/gamma.gif" BORDER=0 >·Asp)], thereby inducinga conformational transition within the NGF amino terminus (residues Ser1-Phe12), which constitutes a criticalpart of the receptor binding determinant. In this report, we provide theoretical and experimental data validatingthis structure and suggest a model for the selectivity of the M(II)-NGF interaction. The structures of themodel complexes [M(NH3)3(-O2CCH3)] and [M(HNCH2)3(-O2CCH3)] (mimicking the M(II)-NGF coordinationsite) with first- and second-row divalent transition metal cations Co(II), Ni(II), Cu(II), Zn(II), Rh(II), Pd(II),and Cd(II) were studied by fully optimized ab initio molecular orbital calculations. Regardless of the chemicalnature of the neutral ligands, these cations split into three groups: (i) Ni(II), Cu(II), and Pd(II) (d8 and d9metals), which prefer a square pyramidal coordination; (ii) Co(II), Rh(II) (d7 metals), and Zn(II) (the d10 first-row transition metal), which prefer a triangular bipyramidal environment; and (iii) Cd(II) (the d10 second-rowtransition metal), which has no intrinsic stereochemical preference. It should be noted, however, thatstereochemical preferences of Cu(II) and Zn(II) are minor. Molecular mechanics calculations demonstrate thatparticular geometric features of the M(II)-NGF coordination site are most suitable for metal cations ofintermediate sizes. Taken together with the intrinsic stereochemical preference of transition metal cations,three ions (Zn(II), Cu(II) and Pd(II)) are expected to be specific NGF antagonists, which is consistent with theeffects of these ions on the conformation and biological activities of NGF.