Umuthii-thalidomideyakhunjulwa ngawo-1960 ngoba yabangela ukukhubazeka okukhulu ezinganeni ezisanda kuzalwa, kodwa ngasikhathi sinye yayisetshenziswa kabanzi ekwelapheni i-multiple sclerosis kanye nomdlavuza wegazi, futhi ingakwazi, nezihlobo zayo zamakhemikhali, ukukhuthaza ukubhujiswa kwamangqamuzana amaprotheni amabili athile angamalungu umndeni wamaprotheni avamile "angenazo izidakamizwa" (izici zokuloba) anephethini ethile yamangqamuzana, i-C2H2 zinc finger motif.

Ocwaningweni lwakamuva olushicilelwe kumagazini wamazwe ngamazwe iSayensi, ososayensi be-MIT Boulder Institute nezinye izikhungo bathole ukuthi i-thalidomide nezidakamizwa ezihlobene nayo zinganikeza isiqalo kubacwaningi ukuze bakhe uhlobo olusha lwenhlanganisela elwa nomdlavuza okulindeleke ukuthi luqondise cishe ku-800. izici zokuloba ezabelana nge-motif efanayo. Izici zokuloba zibophezela ku-DNA futhi ziqondise ukuvezwa kwezakhi zofuzo eziningi, ezivame ukucaciswa ezinhlotsheni ezithile zamaseli noma izicubu; lawa maprotheni ahlotshaniswa nomdlavuza amaningi lapho enza iphutha, kodwa abacwaningi bathole ukuthi kungase kube nzima ukuwaqondisa ekuthuthukisweni kwezidakamizwa ngoba izici zokuloba ngokuvamile ziphuthelwa amasayithi lapho ama-molecule ezidakamizwa ehlangana nawo ngokuqondile.

I-Thalidomide kanye nezihlobo zayo zamakhemikhali i-pomalidomide ne-lenalidomide ingahlasela ngokungaqondile okuhlosiwe ngokufaka iphrotheni ebizwa ngokuthi i-cereblon - izici ezimbili zokuloba ezine-C2H2 ZF: IKZF1 kanye ne-IKZF3. I-Cereblon i-molecule ethile ebizwa ngokuthi i-E3 ubiquitin ligase futhi ingalebula amaprotheni athile onakaliswa uhlelo lokujikeleza kwamaselula. Uma ingekho i-thalidomide nezihlobo zayo, i-cereblon ayinaki i-IKZF1 ne-IKZF3; ebukhoneni bazo, ithuthukisa ukuqashelwa kwalezi zici zokuloba kanye nokulebula kwazo ukuze zicutshungulwe.

Indima entsha yelokhumanduloumuthi

I-genome yomuntu iyakwazi ukubhala ngekhodi izinto ezicishe zibe ngu-800 zokuloba, ezifana ne-IKZF1 ne-IKZF3, ezikwazi ukubekezelela ukuguqulwa okuthile ku-C2H2 ZF motif; ukuhlonza izici ezithile ezingasiza ekuthuthukisweni kwezidakamizwa kungasiza abacwaningi bathole ukuthi ingabe ezinye izici zokuloba ezifanayo zingangenwa izidakamizwa ezifana ne-thalidomide. Uma ngabe kukhona isidakamizwa esifana ne-thalidomide, abacwaningi bebengakwazi ukucacisa izakhiwo ze-C2H2 ZF ezibonwa yi-protein cereblon, eyabe ihlola amandlai-thalidomide, i-pomalidomide ne-lenalidomide ukuze zenze ukuwohloka kwe-6,572 ethize okuhlukile kwe-C2H2 ZF motif kumamodeli weselula. Ekugcineni abacwaningi bahlonze amaprotheni ayisithupha aqukethe i-C2H2 ZF azozwela kule mithi, ezine zazo ngaphambili ebezingabhekwa njengeziqondiso ze-thalidomide nezihlobo zayo.

Abacwaningi babe sebesebenzisa izici zokusebenza nesakhiwo se-IKZF1 ne-IKZF3 ukuze baqonde kangcono izindlela zokusebenzisana phakathi kwezinto ezilotshiweyo, i-cereblon kanye ne-thalidomide yazo. Ngaphandle kwalokho, baphinde basebenzisa amamodeli ekhompyutha aguquguqukayo angu-4,661 ukuze babone ukuthi ingabe ezinye izici zokuloba zingabikezelwa ukuthi zizoma nge-cereblon lapho kukhona umuthi. Abacwaningi babonise ukuthi izidakamizwa ezilungiswe ngokufanelekile ezifana ne-thalidomide kufanele zenze i-cereblon ifake ama-isoform athile we-C2H2 ZF transcription factor ukuze iphinde isetshenziswe.