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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. ###