Download @ tin Scruppsfusrencu Iusrnurs

lKtC6Nottb Tonqt Pina Rmd
I-aJolla,C492037
@ tin Scruppsfusrencu
Iusrnurs
Telepbone
619.455,91n
For information:
Robin B. Goldsmirh
(619)ss4-8134
# 10t593
EMBARGOED BY SCIBNCE:
For wire servicesand broadcastnews, october 14, 199313 p.m. pacific Time
For print media, October 15, 1993
Scripps ScientistsSolve Protein Structure that Could Lead
to New Anti-Cancer Drug Design
La Jolla, CA. OctoberL5, 1993- A teamof researchers
led by Drs. StevenReedand John
Tainer at The ScrippsResearchInstinrtehassolvedthe completeatomic structureof a protein
that may leadto the designof a new classof anti*cancerdrugsto stopthe growth of cancer
cells or misprogramtheir cell division, causingthem to self-destruct.
Scientistshave long soughtthe developmentof so-called"magicbullets" to kill cancercells
while leavinghealthycells intact. The Scrippsresearchers
hopethat this classof protein
structures(known as CksHs2)may provide a perfecttargetfor the designof thesemagic
bullets.
CksHs2is a cell cycle regulatoryproteinthat actsas a masterkey for controlling cell division
at two critical points in the process. Progressionto the next phasein the cycle at thesepoints
is madepossibleby the protein.
Using the techniqueof x-ray crystallography,in which x-rays are projectedthroughcrystals
of pure protein to createa distinctive patternthat can be analyzedto measurethe exact
position of eachatom, the scientistswere able to determinehow the protein's structureallows
it to have a centralrole in regulatingthe cell cycle which controlscell division.
MORE
Page 2 -
Scripps Scientists Solve hotein Structure
The work was reportedin the October15 issueof the journal Scienceby the Scrippsteam
including Drs. HansE. Parge,Andrew S. Arvai, DarrenJ. Murtari, StevenI. Reed,and
JohnA. Tainer.
According to Tainer, "Defectsin cell cycle control is a commontrait of all cancers.
Understandingthe structureand function of this protein could be a first step in leading us to
the developmentof more effective anti-cancertherapiesand/or an enhancementof those
currently utilized."
All cells employ mechanisms
termed "checkpointcontrols" to preventinappropriatecell cycle
progressionwhen essentialeventsare blockedor incomplete. For example,cells exposedto
radiationor chemotherapy
undergorepairprior to DNA synthesisand must completethe
synthesisbeforecell division. This regulatorymechanismensuresthat cells do not divide
with unreplicatedDNA, which constitutesa lethal event.
The new structural results showing that the CksHs2protein acts as a central hub for the
assemblyof other moleculesthat regulatecell division at two crucial points in the processimmediatelyprecedingDNA synthesisand cell division - hasbroad implicationsfor the
control of cell growth and for anti-cancerstrategies.
Becausemalignantcells are defectivein at leastsomecheckpointcontrols,the protein may
afford a primary target for the designof drugs to exploit this intrinsic vulnerability. This
could be accomplished
either by promotinga specificcheckpointover-rideor by halting the
runaway growth of malignanttumors.
On the basisof the solutionof the protein's structure,the researchers
have identifiedthree
specific regionspredictedto be biologically important interaction sitesthat are priorities for
testingby site-directedmutagenesis
and targeteddrug design.
###