Prediction of the three-dimensional structures of the nerve growth factor and epidermal growth factor binding proteins (kallikreins) and an hypothetical structure of the high molecular weight complex of epidermal growth factor with its binding protein

Bax, Ben ORCID: https://orcid.org/0000-0003-1940-3785, Ferguson, Geraldine, Blaber, Michael, Sternberg, Michael J. E. and Walls, Peter H. 1993. Prediction of the three-dimensional structures of the nerve growth factor and epidermal growth factor binding proteins (kallikreins) and an hypothetical structure of the high molecular weight complex of epidermal growth factor with its binding protein. Protein Science 2 (8) , pp. 1229-1241. 10.1002/pro.5560020805

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Abstract

We have predicted the three‐dimensional structures of the serine protease subunits (γ‐NGF, α‐NGF, and EGF‐BP) of the high molecular weight complexes of nerve growth factor (7S NGF) and epidermal growth factor (HMW‐EGF) from the mouse submandibular gland (from the X‐ray crystal structures of two related glandular kallikreins). The conformations of three of the six loops surrounding the active site are relatively well defined in the models of γ‐NGF and EGF‐BP, but three other loops are likely to have flexible conformations. Although the amino acid sequence of α‐NGF is closely related to those of γ‐NGF and EGF‐BP, it is catalytically inactive. Model‐building studies on α‐NGF suggested that mutations (in α‐NGF) just prior to the active site serine (195) and an unusual N‐terminal sequence are consistent with α‐NGF having a zymogen‐like conformation (similar to that in chymotrypsinogen). An hypothetical model of the quaternary structure of HMW‐EGF has been constructed using this model of EGF‐BP and the NMR structure of murine EGF. The C‐terminal arm of EGF was modeled into the active site of EGF‐BP based on data indicating that the C‐terminal arginine of EGF occupies the S1 subsite of EGF‐BP. Data suggesting one of the surface loops of EGF‐BP is buried in the HMW‐EGF complex and symmetry constraints were important in deriving a schematic model. A molecular docking program was used to fit EGF to EGF‐BP.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Wiley
ISSN:	0961-8368
Last Modified:	23 Oct 2022 14:03
URI:	https://orca.cardiff.ac.uk/id/eprint/112652

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