Структурно-функциональные исследования дрожжевой оксидазы D-аминокислот методом рационального дизайна (1105750), страница 3

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DAAO также способствует регуляции гормонов, в первую очередь,одним из важнейших регуляторов гормональной секреции является D-Asp [24].Авторами работы [25] было показано, что в организме различных животных,включая человека, в дополнение к обычной DAAO, присутствует другой схожий посвоему каталитическому действию фермент – D-аспартатоксидаза (DASPO). Этосвязано с тем, что DAAO из млекопитающих с D-Asp практически не активны (для11hDAAO значение kcat/КMD-Asp 0,003 с-1мМ-1 [26]), в то время как скоростьпревращения L-аспартата в его D-изомер является одной из самых высоких средиприродных L-аминокислот.Стоит отметить, что в последнее время, подавляющее число статей поисследованию DAAO посвящено изучению физиологической роли hDAAO ворганизме человека и поиску новых ингибиторов этого фермента, которые могутбытьперспективнывлечении,описанныхвыше,нейродегенеративныхзаболеваний2.1.2.

Первичная структура DAAO из различных источниковЗапоследние20летнаблюдаетсяпостепенныйростчислапроаннотированных аминокислотных последовательностей DAAO, что главнымобразом связано с изучением физиологической роли фермента в различныхорганизмах, а также с поисками новых перспективных DAAO для целейбиотехнологии. Однако свойства природных ферментов могут быть изменены иоптимизированы с помощью метода рационального дизайна. Данный методоснован анализе как четвертичных, так и первичных белковых структур, чтопозволяетвыявлятьструктурныеотличияивыбиратьперспективныеаминокислотные замены для придания природному ферменту нужных свойств.12TvaAnigAsflCpoAorNcrVpoKlaSpoRtoMboMafMcaMtuSerMspScoSscaSgrRxyMauOtaSceTpaNspApoAmedCfaAmelEcaHsaBtaSsc_pigMmuRnoMdoGgaMgaTguDreXlaBflNveNviAgaTcaCelIscSmaSstCtrDha-------------------------------------MAKIVVIGAGVAGLTTAL----QLLRKG--HEVTIVSEFTPGDLS-IGYTSPWAGANWLT--FYD-----GGKLADYDAVSYP-----------------------------------MANNRIVMLGAGVSGLTTAY----LLSQDAS-NSITVLAKHMPGDYD-IEYTSPWAGANYLP--VGKA----GSDHERWERNTWP-----------------------------------MSTNNIVILGAGVSGLTTAY----LLSKDAS-NSITVLAKHMPGDYD-IEYASPWAGANYLP--VGKA----SSSHGKWERNTWP-----------------------------------MASNKIVIIGGGVIGLTTAY----LLSKDKS-NVITVAAKHMPGDYD-VEYCSPWAGANFLP--VGAP----GSAHAKWEANTWP-----------------------------------MEQKNVVVIGAGVAGLTTAL----LLSRLPR-YKVVVAAKHMPGDYD-IEYASPWAGANYMP--MSTR----GTKAADWDKDTWA-------------------------------------MSTIVVVGAGVSGLTCAL----QLAKQGG-NTITVVAKHMPGDYD-PEYTSPFAGANVLP--MAP-------EYNRWEGETWP-------------------------------------MSKVVVLGGGVSGLTTALTLV-NKF-KNEINELTVVSSEFPGDYHAHDYTSPWAGANWAS--FAKGN---EPEQIKRDSLTYK-------------------------------------MAKVVVVGAGISGLSVAHSLL-ELYGRDKIEELVIIARDIPGTFTSYDYTSPWAGANWDS--FAAPD---DHAQIKRDTVTYE-------------------------------MTKENKPRDIVIVGAGVIGLTTAW----ILSDLGLAPRIKVIAKYTPEDRS-VEYTSPWAGANFCS--ISAT----DDNALRWDKITYH----------------------------------MHSQKRVVVLGSGVIGLSSAL------ILARKGYSVHILARDLPEDVSSQTFASPWAGANWTP--FMTLTD--GPRQAKWEESTFK---------------------------------MAIGEQQVIVIGAGVSGLTSAI----CLAEAG--WPVRVWAAALPQQTT-----SAVAGAVWGP--RPKE---PVAKVRGWIEQSLH---------------------------------MAIGEQQVIVIGAGVSGLTSAI----CLAEAG--WPVRVWAAALPQQTT-----SAVAGAVWGP--RPKE---PVAKVRGWIEQSLH---------------------------------MAIGEQQVIVIGAGVSGLTSAI----CLAEAG--WPVRVWAAALPQQTT-----SAVAGAVWGP--RPKE---PVAKVRGWIEQSLH---------------------------------MAIGEQQVIVIGAGVSGLTSAI----CLAEAG--WPVRVWAAALPQQTT-----SAVAGAVWGP--RPKE---PVAKVRGWIEQSLH----------------------------------------MLVIGAGVQGLTSGI----VLAEAG--VPVRIRTAERPRDTT-----SAVAGAMWGP--AMLR---PADRVLRWVTRSYA----------------------------------MAARPDVVVLGAGVSGLSTGI----RLVESG--ARVLVRTAAPPAHTT-----SALAGAMVGP--NLSP---PGDPQRAWTDETLR----------------------------METELDDERDGEVVVVGGGVIGLTTAV----VLAERG--RRVRLWTREPAERTT-----SVVAGGLWWP--YRIE---PVALAQAWALRSLD--------------------------------MTHESNSEVIVVGGGVVGLTTAV----VLAEAG--GRVRIRTREPAELTT-----SAVAGGLWWP--YRIE---PEELVGAWALTTLA----------------------------------MTVMAEVIVVGGGVVGLTTAV----TLAERG--LRVRVWSRDPAGATT-----SAVAGALWWP--YRIE---PAERVGDWALATLA-----------------------------MCGMRGRVVARAVVVGCGVAGLSAAI----ALRERG--FGVRVVAREPPERTT-----SAVAAAVWYP--YRAY---PEERVLSWGARTFE--------------------------------MGVMTKADVVVVGGGVIGMTTAL----TLQRRG--AHVTVLTAHDPADTV-----STVAAAVWYP--SHTE---EDPRVLRWARDTHAMRARSTSRPRAPRRRFRGRRDLGRNHRWARATRASAARPHGVVIGAGVVGLHCAL----ALIESGKFSSVRVVAEKTNEGTT-----SAVAAAFWYP--FLTKT-SPEEMSDRWAIESLR---MSTLRRGVLER------------AIVASSRGQAQGQQITVVGAGVIGLTTAV----VLQRDG--HRVQVIAAARGERTT-----SAVAAALWHP--FLAN---PPERVNAWSSRSLD---------------------------------MSD----VTVVGAGVIGLSCAV----RLLEAG--HTVRVYGRDLAPDLT-----SAVAAAVWEP--YLVE---PRDRVAGWSAAALA---------------------------------MTDR---VIVVGAGVIGLTCAV----RLLQAG--HRVDVVARDLPLETT-----SAVAGAFWYP--YRAL---PQDRVAAWSATSYA---------------------------------MPTAPLRITVIGSGVIGLSAAH----ELAAAG--HQVTVAYDQELAECV-----SSVAAAIWFP--YHSE---NSPAADKLLADSLA--------------------------------------MRVTVAGAGIVGLSSAY----RLAEAG--HDVTVVAAAPPAEST-----SAVAGGVVYP--PGRG---SDERIVRWTAASLA--------------------------------------MRVVVIGAGVIGLSTALCIHERYQSVLPSLDVRVYADRFTPLTT-----TDVAAGLCQA--YLSDP-SNPQEA-HWNQQTFD--------------------------------------MRVVVIGAGVIGLSTALCLHERYHPVLPALDVRVYADRFTPFTI-----SDVAAGLSQA--YLSDP-SNPEEV-HWNQQTFD--------------------------------------MRVVVIGAGVIGLSTALCIHDRYQPVLQSLDVRVYADRFTPLTN-----TDVAAGLWQP--YLSNP-SNPQET-HWNQQTFD--------------------------------------MRVVVIGAGVIGLSTALCIHERYHSVLQPLDIKVYADRFTPLTT-----TDVAAGLWQP--YLSDP-NNPQEA-DWSQQTFD--------------------------------------MRVVVIGAGVIGLSTALCIHERYRSVLKSLDVMVYADRFTPLTT-----TDVAAGLWQP--YLSEP-SNPQEA-HWNQQTFN--------------------------------------MRVVVIGAGVIGLSTALCIHERYHSVLQPLDVKVYADRFTPFTT-----TDVAAGLWQP--YTSEP-SNPQEA-NWNQQTFN--------------------------------------MRVAVIGAGVIGLSTALCIHERYHPTQP-LHMKIYADRFTPFTT-----SDVAAGLWQP--YLSDP-SNPQEA-EWSQQTFD--------------------------------------MRVAVIGAGVIGLSTALCIHERYHPAQP-LHMKIYADRFTPFTT-----SDVAAGLWQP--YLSDP-SNPQEA-EWNQQTFD---------------------MDLAVHRSRRMIKGSSTMNVAVIGAGVIGLSTALCLHEHYHHTLRPLSIKVYADRFTPLTT-----SDGAAGFWQP--YLSE---DPQER-AWNQKTFD--------------------------------------MRIAVIGAGVIGLSTALCIHDRFHALVPQLQLEVYADRFTPHTT-----SDGAAGLWQP--YLSDH-GNLQET-LWNKETFE--------------------------------------MRIAVIGAGVIGLSTALCIHDRFHALVPQLQLEVYADRFTPHTT-----SDGAAGLWQP--YLSDH-GNLQET-LWNKETFE--------------------------------------MRVAIIGAGVMGLSSALCIHQQFHSLEPSLELEVYADHFTPHTT-----SDGAAGLWQP--YLSDH-GNLQET-LWKKETFD--------------------------------------MKVCIIGAGVIGLSTAQSIYQHFHSRVSPLTIEVYADIFTPLTT-----SDGAAGLWQP--YLYDK-GNVKET-QWNKDTFN--------------------------------------MHITVVGAGVIGLSTALCIHENYHRIVRPLKIEIYADKFSPLTT-----SDGAAGLWQP--YLYDN-GNTQET-KWNKETFD-------------------------------------MMKVVVVGGGVIGLSSALCVKERCQ----RADVTVVAAEFTPNTT-----GDGAAGIWQP--QLWN--VTQQEL-KWLQWTFD------------------------------------MAPRVAVVGCGVIGATSALEILQSNPS----VRLTVIADTFSPENT-----SDGAAGLLMP--FAVGE-TDPGLVRRWFKETMR--------------------------------------MRIAVVGAGVIGITTAVAMKEAFP----SAELTVFSEAFSPETT-----GDGSAGLWTP--YIIAN-TDEQKILRWSQATHK-------------------------------------MKQIVVIGAGVSGLSVAVQLAEHYYN---VANVTLISENVSPNTT-----GDGSAGLWGP--YYCGN-TPDHKIVKWSSETHT-------------------------------------MLSVAVIGAGVIGLPTALAIQEELGP---KAEVIIFTDKLSPHTT-----GDVSAGLWSP--YLLQN-TPVQQLTKWSKATQD-------------------------------------MPKIAVLGAGINGIASALAIQERLP----NCEVTIIAEKFSPNTT-----SDVAAGLIEP--FLCDD-D-VDRIINWTSATIS------------------------------------MVLRVGVVGGGIIGLTTALKVLETID----NVNVTIIAEHFTPHTT-----GDVAGGFFEP--YLMEG-MTDEKLRHSIKKCIN--------------------------------------MKVGIIGSGIIGLSTAL----AIQENYPNLELIIQADKKDVMVT-----SYGAAGIFRPDPKLLPRSNDDDSFIHWCHLGHE------------------------------------MTSKVVVVGAGVIGLTTAL----QLKRANPDYSISIVAHHLPGDLD-IEYTSPFAGANWHS--FASKN---DRELQELDKPGYW------------------------------------MTS-VVVLGAGVIGLTTAL----ELKRWNPDLDITIAAHHWPGDIH-PSYTSPYAGANWQS--FASPE---DKELQEIDKPGYK------------------------------------MRPKIVVIGAGVSGLTTAL----ELKKSSSEYDVTVVAQHLPGDYD-VNYVSPYAGANWYS--FATPE---DKVLQAFDKPSYR697373737368767778767171717164707672707572108896768716673737373737372728873737373736972707272707273747374TvaAnigAsflCpoAorNcrVpoKlaSpoRtoMboMafMcaMtuSerMspScoSscaSgrRxyMauOtaSceTpaNspApoAmedCfaAmelEcaHsaBtaSsc_pigMmuRnoMdoGgaMgaTguDreXlaBflNveNviAgaTcaCelIscSmaSstCtrDhaILRELARSSPEAGIRLIN---QRSHVLKRDLP-KLEGAMSA~ICQRNPWFKNTVDSFEIIEDRSRIVHD-----DVAYLVEFASVCIHTGVYLNWLMSQCLSLGA---TVVKR-RVNHIKALRELTKNHPEAGIHFQE---TIVYNRTKDQGSATGEWFSE-LVQKDPWYMEVVPDFQDIP--ADQLAP-----GIDNASKFTSVCINTAVYLPWLVGQCRKNGV---VFKRAVLKHVADALKEITEKYPEAGIHFQD---AIVYNRTKDQGSATGDWFSE-LVQKEPWYKDVVPDFRNFP--DNELAP-----GIDNASVFTSVCINTAIYLPWLIGQCRKTGV---VFKRAVIKHVADVFEDLARNNPEAGIHFQD---SIIYNRLKDASSDTAVWFKE-LINPNPWYKDIVPDFRPIP--KEKLPH-----GFDNGSCFTSVCLNAPVYLAWLVSQCRKNGV---VFKRAVFKHIVDALEDLARNHPDAGIHFQE---CEIHSRSKDVGTTTAKWFGE-LLSPSPWFKDVVPNFCTLP--KSRHGP-----GFDSVTVFTSVCINTAVYLPWLVSQCLKNGV---VFKRAVFNHILDELKRLAETCPEAGIHFQK---AVLYRRAQDEAAGFAGPLSDGLFVRNPWYKDLVPDYVDLP--ASEVPE-----GMSSASSFTSVCINTAIYLPWLVGQCRARGV---VFKRAVLKHISDKFMELADTEPSSGIKKFP---LKYFIRKNDMIPWYIEG----------KFVRDIEYLSDDELITRNLNP-----EEYIGIQFTTVTVTPIIYNNYLIGLLKKSGV---IIKRIPRINDIEWFTELARSKPETGVKEYT---LKLVTRK-ETIPWFVRD----------NFVRDLKQMSEEELKYRNLDP-----QDYHGFEFTTFTVTPSTYKFWMVNEIKKMGG---KLRQLAKIDAIERFAYLAKTRPEAGIRFAD---LRELWEYEPKHDKIRS------------WNTYVRDFKVIP--EKDLPG-----ECIYGHKATTFLINAPHYLNYMYKLLIEAGV---EFEKKELSHIKEKWVELVPTGHAMWLKGTR---RFAQNEDGLLG---------------HWYKDITPNYRPLP--SSECPP-----G-AIGVTYDTLSVHAPKYCQYLARELQKLGA---TFERRTVTSLEQVFRDLAKDPA-TGVRMT---PALSVGDRIETG-------------AMPPGLELIPDVRPADP--ADVPG-----GFRAGFHATLPMIDMPQYLDCLTQRLAATGC---EIETRPLRSLAEVFRDLAKDPA-TGVRMT---PALSVGDRIETG-------------AMPPGLELIPDVRPADP--ADVPG-----GFRAGFHATLPMIDMPQYLDCLTQRLAATGC---EIETRPLRSLAEVFRDLAKDPA-TGVRMT---PALSVGDRIETG-------------AMPPGLELIPDVRPADP--ADVPG-----GFRAGFHATLPMIDMPQYLDCLTQRLAATGC---EIETRPLRSLAEVFRDLAKDPA-TGVRMT---PALSVGDRIETG-------------AMPPGLELIPDVRPADP--ADVPG-----GFRAGFHATLPMIDMPQYLDCLTQRLAATGC---EIETRPLRSLAEEFTALCRDSA-SGVHLA---PGR-MAARFDLGD------------VVPPEAHLLDDLRKCTP--DELPE-----GFVSGYHATVPLIDMPKYLDHLVDRFRAAGG---ELVVSPVPTLGEVLG---AEPL-PGVAWR---DGT-LAARPEGA--------------TPPFADQTPGFRSLGD--DERPA-----GFGTAFTVRLPLVDMPVYLAYLLERFRDAGG---EVRVAPVASLDEVYEELAARPGQTGVRML---EGVLGETGLDEV--------------DGWAAARLPGLRAASA--AEYAG--------TGLWARLPLIDMSTHLPWLRERLLAAGG---TVEDRAVTDLAEVYEELAARSDETGVRMV---EGVHGGTRLDGL--------------GAWAS-RVAGLRAATA--GEYPG--------VGLWARLPLVDMPVHLRWLRERFVAAGG---VVESRTVTDLAAVYEELSGAPRETGVRRV---AGLHGGERLAAL--------------GAWSA----GLR--DA--VEVP---------EGLRVTLPLLDMPVHLAWLERRLAAAGG---AVERRAVTGFAEVFRGLAADPR-TGVRLG---EGVELLRRSAPG--------------EPWWREAVSGFRRCRE--EELPP-----GCRGGYRFVAPVAEMPAYLAYLLDRLRGAGG---TLELREVSSLEEELRRQAADGVPGVIDRP---TRMWLRHRYAGP---------------PWWADACGDLT-AEP--AEPP-------YTALLRFTAPSVEMTPYLAWLRQRLEAGGG---RIVGRALGTLAEWYEEVERSDREAKTQSSGVEIRRFKFYLREQKE------------KPAWAAALMHHRELEVG--EYDES-----RYAGGFEFDAPVAAMSTFLPWLLERCERAGV---QFDWRKISSVEDELTRIANEHPEAG-------VDLLTAREAADDT------------RLPWWAPSVPDLALEPG--PHPLG------APYSLRFTAPRIEPSLHLPWLEAQLDCPVR---AEHVRSLAEVEGEFTSLAERG-ADGVVMT---SGTEIFRQPVGE---------------PWWS--VAVPEVHRV--AEPRP-----GYAEGWSFVAPVIEMPIYLPWLAGRVCELGG---TVEQRTVTSLDDVFDALADTDPESGVRMV---AGTEVFMAPEPD---------------PWWG--AAVPGLTRT--RDVPP-----GWVDGWTFTTPVVDTGVYLAWLAGRVEQLGG---TITRLNLSALPSRFEQLSEHP-ETGIDLR---RGLNVDHLPGAD---------------RSWTRIVAGTEEASP--ADLPD-----GAHAGVWATVPIITMSTYLGWLRGRVEELGA---DFAKGTVTDLAQVFRGQDAPG----VRFR---RGRVLLPAGTPD---------------PQWLP--AVEAAVRD--GD------------RVEFTTAVVDTPVYLEWLRERVAGLGV---RVEYRTLTALSSYLLSHIHSPNAASMGLALI-SGYNLFHETIP---------------DPSWKDAVLGFRRLTRRELDMFP-----NYSYGWFNTSLIVEGRRYLEWLTKRLTERGV---KFFQQKVESFEEYLLSHIHSPNAANMGLALI-SGYNLFREAFP---------------DPSWKDTVLGFRKLTCRELDMFP-----DYSYGWFNTSLIVEGRRYLPWLTKRLTERGV---KFFQRKVESFEEYLLSHLHSPNAADMGLALI-SGYNLFHEAVP---------------DPSWKDIVLGFRKLTPRELDMFP-----DYSYGWFNTSLILEGKRYLQWLTERLTERGV---KFSQRKVESLEEYLLSHVHSPNAENLGLFLI-SGYNLFHEAIP---------------DPSWKDTVLGFRKLTPRELDMFP-----DYGYGWFHTSLILEGKNYLQWLTERLTERGV---KFFQRKVESFEEYLLSLIGSPNAANMGLAPV-SGYNLFREAVP---------------DPYWKDIVLGFRKLTLRELDMFP-----DYSYGWFNTSLILEGRKYLQWLTERLTERGV---KFFLWKVESFEEYLLSHIGSPNAANMGLTPV-SGYNLFREAVP---------------DPYWKDMVLGFRKLTPRELDMFP-----DYRYGWFNTSLILEGRKYLQWLTERLTERGV---KFFLRKVESFEEYLLSCLHSPNAEKMGLALI-SGYNLFRDEVP---------------DPFWKNAVLGFRKLTPSEMDLFP-----DYGYGWFNTSLLLEGKSYLPWLTERLTERGV---KLIHRKVESLEEHLQSCLHSPNAEKMGLALI-SGYNLFRDEVP---------------DPFWKSTVLGFRKLTPSELDMFP-----DYSYGWFNTSLLLEGKSYLSWLTERLTERGV---KFIHRKVASFEEYLLGYLGSPEAKKMGLFLL-SGYNLFPKAVP---------------DPSWKDTVLGFRKLTPRELELFP-----GYSYGWINTSMILEAKSYLPWLTQRLTERGV---KFFQRKVHSFEEHLLGYLNSPEAKEMGLFLI-SGYNLFKQPVP---------------DPSWKNIVLGFRNLTPKELELFP-----GYSYGWFNTALMLECRSYLPWLTNRLAQRGV---KFFHRKVESFEEHLLGYLNLPEAKEMGLFLI-SGYNLFKQPVP---------------DPSWKNIVLGFRNLTPKELELFP-----GYSYGWFNTALMLECRSYLPWLTNRLAQRGV---KFFHRKVESFEEYLLGHLHSPAATEMGLFLI-SGYNLFTEPVP---------------DPSWKNIVLGFRNLTPKELELFP-----GYSYGWFNTALMLEGRSYLPWLTNRLTQRGV---KFFHKKVESFQEYLLSFINSPDSVKMGIFLQ-SGYNLCAEPMP---------------EPSFKQAVLGFRQLSKRELEMFP-----GYSFGWFNTALMIEGKTYLPWLMNWLKQRGV---TFFQRTIDSFKEHLLKFVHSSEAPNMGLFLQ-SGYNILKEPAP---------------EPSWKDIILGFRHLTPEELELFP-----GYSYGWFNTAIMIEGKHYLPWMMKRLEERGV---KFVHKRIESFGEHLSRLYKTEFSHRIGLFCQ-SGYNVFDKEVP---------------DPPWKDIVLGFRHLTEDEVKKFP-----GYSYGWFNTTLMLECRSYLPWLTQRLKEKGV---KFEQRKIASLSERFEELLRSEIAPELGVFRA-SGCLVADHQQE---------------IPDWKDLVYGFKQMSREELERFPL----SAKIGFVFETIIAQGSYYIPWLMKRIQHYGG---KIVKRRLDSFQEWLEIFWKSEMASDVGVSLL-PSYRLTSSSEGLP-------------VPVWGDVVYGCSKLNKKQLERLSKTNEKNYTAGYHYITYTCEPTKMLPFLMKKLRSMNV---RIVKTKIKDLKKFFHQLWKNGLGGKIGVCLQ-PCMRLTTDPNGYP-------------EPAWKEIVFGCQKIQEPELKRLSNEHGRSYTGGYHFATFTCEPSGLLPYLFNRFIAVGG---KFVASKVRNFDEYILKLWKNGDAKTTGISLQ-LIMALSNKKD-YK-------------APEWLKISLGHSEFTQDRLKYYSQRYGEEFTGGYAFVGFIWEPVRFLPYLEKKFKDRGG---QIRMGRVENFAERIHEYQADG---NPGAEEQ-SGYWLQSVKS----------------EPKWLKLMKNVHILTDAEMKQVARRPEHKF--GIFYTTWYLEPTPYIKWCTDKFLKNGG---KFKKQKIENIDDTFEKKKKRYASCTNAKQTL-KKNVQTVTTR------------------KQANIRVKYSRKRES-VQSCSTVKQTLHVSFYVLKLRILTFQPCTLFVSSSLASRGC---HFVRKKLDTLDQQYWKLACSWDSSEAGVYFH---------------------------------PTYQLSEYYEFDIPFIT----------YYYTTCIIEPRYYMNYLLKKLTKLIPNDHSIYSERMTRFTSKFLELS-NEPRSGVWITT---NKSYVTEVEFN--SKG---RDPAKFVPWFKNFVKNFKTIEN-SSELPD-----GIAFGYSFDGVVISVPIYLNYLLQENLGAGN---SVRRISKISNIHKFLQLAESDPRAGVWATE---NLSYYTDYEVS--AAK---GNFKEIIPWYRDFVDDFKIID--SSKLPA-----GIAFGHSFKGLVVSVPTYLKYLVQQNKEIGN---KLKKVPIIYNIEAFMELAQNEPRSGIWHKM---SYAYFTEDYMK--EIN---YDTGKGIPWFKDFVEEFKILE--KKELPE-----GILFGFSFKGVVISVPIYLNFLLSKALENGI---AIKRVKAIENVETvaDANLL-HSSGSRPDVIVNCSGLFARFLGGVED----KKMYPIRGQVVLVRNSLPF-MASFSSTPE-KENEDEALYIMTRFDGT-SIIGGCFQPNNWSSEPDPSLTHRILSRALDRFPELT 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Рис.

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