LANDELA
Ubuchule obutsha obutsha obuphuhliswe liqela lezenzululwazi kwiZiko loLawulo lweGenomic (CRG) e-Barcelona lifumene ubukho bobuninzi 'bolawulo olukude' olulawula ukusebenza kweeprotheyini kwaye ezinokuthi zisetyenziswe njengeethagethi zokuphumeza amachiza asebenzayo. kunye nokusebenza kakuhle kwiipathologies ezahlukeneyo ezinje ngedementia, umhlaza kunye nosulelo olusulelayo.
Ezi 'zilawuli zikude' zaziwa ngokwesayensi njengeziza ze-allosteric. Ezi zizilawuli ezikude ezikude kwindawo yesenzo seprotheni, kodwa zinamandla okulawula okanye ukumodareyitha ", uJúlia Domingo, umbhali wokuqala wokufunda, opapashwe ngolwesiThathu kwiphephancwadi elithi "Nature". wacacisela uABC. Kwaye wongeza umzekeliso: "Kungathi ngesi silawuli kude ungakhanyisa kwaye ucime ibhalbhu okanye ulawule ubunzulu besibane."
Kule meko apho ihlose ukuvimba okanye ukulawula umsebenzi weeprotheni ezigcina umsebenzi wazo otshintshileyo ekuvalelweni. Umzekelo, kwimeko yomhlaza, iiprotheyini eziye zafumana uguquko ziye zatshintshwa ukusebenza kwazo, zenza ngokungaqhelekanga kwaye iseli ikhula ngokungaqhelekanga. Kwiimeko ezininzi, akukho ziyobisi ezinokumodareyitha okanye zithintele lo msebenzi ungaqhelekanga okanye, ukuba zikhona, azikho ngqo kwaye zikhutshwe kwezinye iiprotheni ezisebenza ngokuqhelekileyo.
Ngokwemveli, abazingeli beziyobisi baye baqulunqa unyango olujolise kwindawo esebenzayo yeprotheni, ummandla wayo omncinci uvelisa ukusabela kweekhemikhali apho iithagethi zibophelela khona. I-drawback yala machiza, eyaziwa ngokuba yi-orthosteric drugs, kukuba iindawo ezisebenzayo zeeprotheyini ezininzi zifana kakhulu kwaye iziyobisi zibophe kwaye zithintele iiprotheyini ezininzi ezahlukeneyo ngexesha elinye, kwanabo basebenza ngokuqhelekileyo kwaye abanomdla ukuba bachukumise. kunokubangela iziphumo ebezingalindelekanga.
“Kulapho wangena kwingqikelelo yeallosteria kunye namandla enawo ukuyila amayeza. Into enomdla malunga neziza ze-allosteric kukuba zichanekileyo kakhulu kwiprotheni nganye. Ukuba ezi ndawo ze-allosteric zifumana indawo yeproteni apho iyeza linokuhla khona, liya kuba lithe ngqo kakhulu kuloo proteni. Siyakukwazi ukunqwenela amayeza asebenzayo ngakumbi”, utshilo umphandi.
“Asipheleli nje ekufumaniseni ukuba ezi ndawo zonyango zininzi, kodwa kukho ubungqina bokuba zinokulawulwa ngeendlela ezininzi ezahlukeneyo. Endaweni yokuba sizivule kwaye sizicime nje, sinokumodareyitha umsebenzi wazo njenge-thermostat. Ukusuka kwimbono yobunjineli, kufana nokuba sibethe igolide, kuba isinika indawo eninzi yokuyila 'iziyobisi ezihlakaniphile' eziya ezimbi kwaye zitsibe okulungileyo, "uchaza u-André Faure, umphandi we-postdoctoral kwi-CRG. kunye nomlobi wokuqala wenqaku.
umfanekiso omacala amathathu obonisa iprotheni yomntu PSD95-PDZ3 ukusuka kwiindawo ezahlukeneyo zokujonga. Imolekyuli iboniswa ibophelela kwindawo esebenzayo ngomthubi. I-Blue to red color gradient ibonisa iindawo ezinokwenzeka ze-allosteric - André Faure / ChimeraX
Kule nto yokufunyanwa, iqela lisebenzise indlela evumela ukuba bathathe iprotheni kunye nefom yenkqubo kunye nokudibana kwehlabathi kunye nazo zonke iziza. Ukwenza oku, bakhethe iiprotheyini ezimbini ezininzi kakhulu kwiproteome yethu yabantu. “I-50% yomphezulu weprotein inamandla e-allosteric. Indlela yethu yenza kube nokwenzeka ukwenza iatlasi yeziza zeallosteric, eziya kwenza inkqubo yokukhangela amachiza asebenzayo isebenze ngakumbi”, uqinisekisa uJúlia Domingo.
Ababhali bophononongo baphuhlise ubuchule obubizwa ngokuba yi-double-depth PCA (ddPCA), abayichaza ngokuba "yi-brute force experiment." "Senza ngabom izinto ngamawaka eendlela ezahlukeneyo zokwenza umfanekiso opheleleyo wendlela into esebenza ngayo," kuchaza uNjingalwazi woPhando we-ICREA uBen Lehner, uMququzeleli weNkqubo yeBiology ye-CRG kunye nombhali wophononongo. “Kufana nokuba ukrokrela ukuba i-spark plug imbi, kodwa endaweni yokuyijonga nje loo nto, umkhandi uya kuyicalula yonke imoto aze ajonge zonke iindawo nganye nganye. Ngokuhlalutya izinto ezingamawaka alishumi ngaxeshanye, sichonga zonke izinto ezibaluleke ngokwenene.”
Okulandelayo, sisebenzisa i-algorithms yobukrelekrele bokwenziwa ukutolika iziphumo zelebhu.
Enye yeenzuzo ezinkulu zendlela, ukongeza ekwenzeni lula inkqubo eyimfuneko yokufumana iziza ze-allosteric, kukuba yindlela efikelelekayo nefikelelekayo kuyo nayiphi na ilabhoratri yophando emhlabeni. “Ifuna nje ukufikelela kwii-reagents zebhayoloji ezisisiseko, ukufikelela kwi-DNA sequencer kunye nekhompyuter. Ngala macandelo mathathu, nayiphi na ibhubhoratri kwiinyanga ezi-2-3, kunye nohlahlo lwabiwo-mali oluncinci, inokuqhuba olu vavanyo kwiprotheni yomdla abayifunayo ", uqinisekisa uJúlia Domingo. Ithemba labaphandi lelokuba izazinzulu zethu ziya kusebenzisa ubuchule ngokukhawuleza nangokubanzi imephu yeendawo ze-allosteric zeeproteni zabantu nganye nganye. "Ukuba sinedatha eyaneleyo mhlawumbi ngenye imini singahamba inyathelo elinye ukuya phambili kwaye siqikelele ukusuka kulandelelwano lweprotheyini ukuya ekusebenzeni. Sebenzisa ezi datha ukubakhokela njengonyango olungcono ukuqikelela ukuba utshintsho oluthile kwiprotheni luya kuhla lube sisifo ", uqukumbele umphandi.
