PMID- 18291418
OWN - NLM
STAT- MEDLINE
DCOM- 20080527
LR  - 20211203
IS  - 1089-8638 (Electronic)
IS  - 0022-2836 (Linking)
VI  - 377
IP  - 3
DP  - 2008 Mar 28
TI  - Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET 
      receptor antagonist.
PG  - 616-22
LID - 10.1016/j.jmb.2008.01.034 [doi]
AB  - The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) 
      and its receptor MET, the tyrosine kinase encoded by the c-MET proto-oncogene, 
      exert major roles in cancer invasion and metastasis and are key targets for 
      therapy. NK1 is an alternative spliced variant of HGF/SF that consists of the 
      N-terminal (N) and first kringle (K1) domains and has partial agonistic activity. 
      NK1 crystallizes as a head-to-tail dimer with an extensive inter-protomeric 
      interface resulting from contacts between the two short interdomain linkers and 
      reciprocal contacts between the N and K1 domains. Here we show that a subset of 
      mutants at the NK1 dimer interface, such as the linker mutants Y124A or N127A or 
      the kringle mutant V140A:I142A, bind the MET receptor with affinities comparable 
      to wild-type NK1 but fail to assemble a dimeric, signalling competent NK1-MET 
      complex. These NK1 variants have no detectable agonistic activity on, behave as 
      bona fide receptor antagonists by blocking cell migration and DNA synthesis in 
      target cells and have strong prospects as therapeutics for human cancer.
FAU - Youles, Mark
AU  - Youles M
AD  - Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
FAU - Holmes, Oliver
AU  - Holmes O
FAU - Petoukhov, Maxim V
AU  - Petoukhov MV
FAU - Nessen, Merel A
AU  - Nessen MA
FAU - Stivala, Simona
AU  - Stivala S
FAU - Svergun, Dmitri I
AU  - Svergun DI
FAU - Gherardi, Ermanno
AU  - Gherardi E
LA  - eng
GR  - G0501019/MRC_/Medical Research Council/United Kingdom
GR  - G0800025/MRC_/Medical Research Council/United Kingdom
GR  - G9704528/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080118
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Alternative Splicing
MH  - Animals
MH  - Cell Line
MH  - Cell Movement
MH  - Cloning, Molecular
MH  - DNA Replication
MH  - Dimerization
MH  - Dogs
MH  - Hepatocyte Growth Factor/*chemistry/genetics/metabolism
MH  - Humans
MH  - Mice
MH  - Models, Molecular
MH  - Mutation
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Mas
MH  - Proto-Oncogene Proteins c-met/*antagonists & inhibitors/metabolism
EDAT- 2008/02/23 09:00
MHDA- 2008/05/28 09:00
CRDT- 2008/02/23 09:00
PHST- 2007/08/15 00:00 [received]
PHST- 2007/12/22 00:00 [revised]
PHST- 2008/01/14 00:00 [accepted]
PHST- 2008/02/23 09:00 [pubmed]
PHST- 2008/05/28 09:00 [medline]
PHST- 2008/02/23 09:00 [entrez]
AID - S0022-2836(08)00065-X [pii]
AID - 10.1016/j.jmb.2008.01.034 [doi]
PST - ppublish
SO  - J Mol Biol. 2008 Mar 28;377(3):616-22. doi: 10.1016/j.jmb.2008.01.034. Epub 2008 
      Jan 18.