PDBsum entry: 1nk1

Hormone/growth factor

PDB id: 1nk1

Contents

Protein chains

172 a.a. *

Waters ×59

* Residue conservation analysis

PDB id:

1nk1

Name:

Hormone/growth factor

Title:

Nk1 fragment of human hepatocyte growth factor/scatter factor (hgf/sf) at 2.5 angstrom resolution

Structure:

Protein (hepatocyte growth factor precursor). Chain: a, b. Fragment: nk1. Synonym: scatter factor, sf, hepatopoeitin a. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: mrc5. Organ: lung. Cell: fibroblast. Cellular_location: extracellular. Gene: hepatocyte growth factor/scatter factor. Expressed in: pichia pastoris.

Biol. unit:

Dimer (from PQS)

Resolution:

2.50Å R-factor: 0.245 R-free: 0.319

Authors:

D.Y.Chirgadze,J.P.Hepple,H.Zhou,R.A.Byrd,T.L.Blundell, E.Gherardi

Key ref:

D.Y.Chirgadze et al. (1999). Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding. Nat Struct Biol, 6, 72-79. PubMed id: 9886295 DOI: 10.1038/4947

Date:

20-Aug-98 Release date: 13-Jan-99

Protein chains

P14210  (HGF_HUMAN) -  Hepatocyte growth factor

Seq: 728 a.a.

Struc: 172 a.a.

DOI no: 10.1038/4947

Nat Struct Biol 6:72-79 (1999)

PubMed id: 9886295

Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding.

D.Y.Chirgadze, J.P.Hepple, H.Zhou, R.A.Byrd, T.L.Blundell, E.Gherardi.

ABSTRACT

Although ligand-induced receptor dimerization is a common prerequisite for receptor activation, the mode by which different growth factors bind their receptors and cause them to dimerize varies considerably. Here we report the crystal structure at 2.5 A resolution of NK1, a receptor-binding fragment and a natural splice variant of hepatocyte growth factor/scatter factor (HGF/SF). NK1 assembles as a homodimer in the asymmetric unit, revealing a novel mode of growth factor dimerization produced by close packing of the N domain of one subunit and the kringle domain of the other, thus bringing the two linkers in close proximity. The structure suggests the presence of a binding site for heparan sulfate chains and a mechanism by which the NK1 dimer may engage two receptor molecules through clusters of amino acids located on each protomer and on opposite surfaces of the homodimer. We also report that short (14-mer) heparin fragments effectively dimerize NK1 in solution, implying that heparan sulfate chains may stabilize the NK1 dimer. These results provide a basis for the agonistic activity of NK1 and have implications for the mechanism of receptor binding of HGF/SF.

Selected figure(s)

Figure 1.
Figure 1. Schematic representation of the domain structure of HGF/SF. The N-terminal (N) domain is shown as a triangle, the kringle (K) domains are shown as circles and the catalytically inactive serine proteinase domain as a rectangle. Also shown is the location of the trypsinlike site between the C-terminal kringle and the serine proteinase domain that is cleaved during activation of pro-HGF/SF. The lines with arrows below the figure indicate the domain composition of the NK1 and NK2 fragments of HGF/SF.

Figure 2.
Figure 2. a, Ribbon representation of the NK1 homodimer observed in the crystal's asymmetric unit. The view is along a non-crystallographic two-fold axis. Protomers A and B are shown in blue and green, respectively. The N and kringle domains of each protomer are labeled as N and K. The disulfide bridges are shown in yellow. The linker (residues Lys 122−Asn 127) of each protomer is shown in magenta for protomer A and orange for protomer B. b, Side view of the NK1 homodimer shown in (a) (same color coding). Protomer B (green) is located behind protomer A (blue). The amino- and carboxy-termini are labeled. The figure was generated with SETOR^50.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 72-79) copyright 1999.

Figures were selected by the author.