1gmn

From Proteopedia

Revision as of 14:09, 5 November 2007

CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR

Overview

NK1 is a splice variant of the polypeptide growth factor HGF/SF, which, consists of the N-terminal (N) and first kringle (K) domain and requires, heparan sulfate or soluble heparin for activity. We describe two X-ray, crystal structures of NK1-heparin complexes that define a heparin-binding, site in the N domain, in which a major role is played by R73, with further, contributions from main chain atoms of T61, K63 and G79 and the side, chains of K60, T61, R76, K62 and K58. Mutagenesis experiments demonstrate, that heparin binding to this site is essential for dimerization in, solution and biological activity of NK1. Heparin also comes into contact, with a patch of positively charged residues (K132, R134, K170 and R181) in, the K domain. Mutation of these residues yields NK1 variants with, increased biological activity. Thus, we uncover a complex role for heparan, sulfate in which binding to the primary site in the N domain is essential, for biological activity whereas binding to the K domain reduces activity., We exploit the interaction between heparin and the K domain site in order, to engineer NK1 as a potent receptor agonist and suggest that dual, (positive and negative) control may be a general mechanism of heparan, sulfate-dependent regulation of growth factor activity.

About this Structure

1GMN is a Single protein structure of sequence from Homo sapiens with EPE as ligand. Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor., Lietha D, Chirgadze DY, Mulloy B, Blundell TL, Gherardi E, EMBO J. 2001 Oct 15;20(20):5543-55. PMID:11597998

Page seeded by OCA on Mon Nov 5 16:15:17 2007