PMID- 9886295
OWN - NLM
STAT- MEDLINE
DCOM- 19990129
LR  - 20091119
IS  - 1072-8368 (Print)
IS  - 1072-8368 (Linking)
VI  - 6
IP  - 1
DP  - 1999 Jan
TI  - Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth 
      factor dimerization and receptor binding.
PG  - 72-9
AB  - 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.
FAU - Chirgadze, D Y
AU  - Chirgadze DY
AD  - Department of Biochemistry, University of Cambridge, UK.
FAU - Hepple, J P
AU  - Hepple JP
FAU - Zhou, H
AU  - Zhou H
FAU - Byrd, R A
AU  - Byrd RA
FAU - Blundell, T L
AU  - Blundell TL
FAU - Gherardi, E
AU  - Gherardi E
LA  - eng
SI  - PDB/1NK1
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Struct Biol
JT  - Nature structural biology
JID - 9421566
RN  - 0 (Peptide Fragments)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Hepatocyte Growth Factor/*chemistry/metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Peptide Fragments/chemistry/metabolism
MH  - *Protein Conformation
MH  - Proto-Oncogene Proteins c-met/metabolism
EDAT- 1999/01/14 03:01
MHDA- 2001/03/23 10:01
CRDT- 1999/01/14 03:01
PHST- 1999/01/14 03:01 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/01/14 03:01 [entrez]
AID - 10.1038/4947 [doi]
PST - ppublish
SO  - Nat Struct Biol. 1999 Jan;6(1):72-9. doi: 10.1038/4947.