Mushongathalidomideyakarangarirwa muma1960s nekuti yakakonzera kuremara kunoparadza muvana vachangozvarwa, asi panguva imwechete yaishandiswa zvakanyanya kurapa multiple sclerosis nemamwe kenza eropa, uye inogona, pamwe nekemikari hama, kukurudzira kuparadzwa kwemasero maviri chaiwo mapuroteni ayo ari nhengo dze mhuri yezvakajairwa "zvisina zvinodhaka" mapuroteni (zvinyorwa zvinyorwa) zvine chimiro chemolecular chaiyo, iyo C2H2 zinc finger motif.

Muongororo ichangoburwa yakabudiswa mupepanhau repasi rose reScience, masayendisiti kubva kuMIT Boulder Institute nemamwe masangano akawana kuti thalidomide nemishonga ine hukama inogona kupa pekutangira kuti vaongorori vagadzire rudzi rutsva rweanorwisa cancer anotarisirwa kunanga mazana masere. zvinyorwa zvinogovera zvakafanana motif. Zvinyorwa zvinyorwa zvinosunga kuDNA uye kurongedza kutaura kwemajini akawanda, ayo anowanzo tarisa kune mamwe marudzi emasero kana matishu; mapuroteni aya ane chekuita negomarara mazhinji kana akanganisa, asi vaongorori vakaona kuti zvingave zvakaoma kuvanangidzira kuti vagadzirise zvinodhaka nekuti zvinyorwa zvekunyora zvinowanzopotsa nzvimbo uko mamorekuru ezvinodhaka anosangana nawo zvakananga.

Thalidomide nehukama hwayo hwemakemikari pomalidomide uye lenalidomide inogona kurwisa zvinangwa zvavo zvisina kunanga nekunyora puroteni inonzi cereblon - zvinhu zviviri zvinyorwa zvine C2H2 ZF: IKZF1 uye IKZF3. Cereblon imorekuru inodaidzwa kuti E3 ubiquitin ligase uye inogona kunyora mapuroteni chaiwo ekudzikisirwa neserura circulatory system. Mukusavapo kwethalidomide nehama dzayo, cereblon inofuratira IKZF1 uye IKZF3; pamberi pazvo, zvinokurudzira kucherechedzwa kwezvinhu izvi zvekunyora uye kunyora kwavo kuti zvigadziriswe.

Basa idzva reizviyekaremushonga

Iyo genome yemunhu inokwanisa kukodha zvingangoita mazana masere ezvinyorwa zvinyorwa, zvakaita seIKZF1 neIKZF3, izvo zvinokwanisa kushivirira mamwe shanduko muC2H2 ZF motif; kuziva zvinhu zvinogona kubatsira mukugadzirwa kwezvinodhaka kunogona kubatsira vaongorori kuona kana zvimwe zvakafanana zvekunyora zvichibatwa nemishonga yakaita sethalidomide. Kana chero mushonga wakaita sethalidomide uripo, vaongorori vaigona kuona chaiyo C2H2 ZF zvivakwa zvakacherechedzwa neprotein cereblon, iyo yakabva yaongororwa kugona kwe.thalidomide, pomalidomide uye lenalidomide kukonzeresa kuderedzwa kwe6,572 chaiyo C2H2 ZF motif akasiyana mune cellular modhi. Pakupedzisira vatsvakurudzi vakacherechedza mapuroteni matanhatu eC2H2 ZF-aizove ane hanya nemishonga iyi, ina iyo yakanga isati yamboonekwa sezvinangwa zvethalidomide nehama dzayo.

Vatsvakurudzi vakabva vaita maitiro ekushanda uye maitiro eIKZF1 neIKZF3 kuti anzwisise zviri nani nzira dzekubatana pakati pezvinyorwa zvinyorwa, cereblon uye thalidomide yavo. Kunze kwezvo, vakamhanyisawo 4,661 mutational makomputa mamodhi kuti vaone kana zvimwe zvinyorwa zvinyorwa zvingafungidzirwa kuti zvichamira necereblon pamberi pemushonga. Vatsvagiri vakaratidza kuti zvakagadziridzwa thalidomide-senge zvinodhaka zvinofanirwa kukurudzira cereblon kuisa tag chaiyo isoforms yeC2H2 ZF transcription factor kuti iitezve.