Table A. Sequence Alignment of the Catalytic Domain of Human and Protozoan Pdes

Plasmodium falciparum phosphodiesterases are hPDE9A-like with a hPDE1 active site. Considerations for antimalarial drug design. Brittany L. Howard, Philip E. Thompson, David T. Manallack

Table A. Sequence alignment of the catalytic domain of human and protozoan PDEs.

*h1********** *h2****

CN1A_HUMAN RKTYHMVGLAYPAAVIVTLKDVDKWSFDVFALNEASG---EH 173

CN1C_HUMAN RRTSNMVGLSYPPAVIEALKDVDKWSFDVFSLNEASG---DH 183

CN1B_HUMAN RRTYTSVGPTYSTAVLNCLKNLDLWCFDVFSLNQAAD---DH 178

CN3A_HUMAN DKPILAPEPLVMDNLDSIMEQLNTWNFPIFDLVENIGRKCGR 709

CN3B_HUMAN IEQEVSLDLILVEEYDSLIEKMSNWNFPIFELVEKMGEKSGR 694

CN4A_HUMAN NIPRFGVKTDQEELLAQELENLNKWGLNIFCVSDYAG---GR 389

CN4B_HUMAN SISRFGVNTENEDHLAKELEDLNKWGLNIFNVAGYSH---NR 362

CN4C_HUMAN TVPRFGVQTDQEEQLAKELEDTNKWGLDVFKVAELSG---NR 344

CN4D_HUMAN SIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSG---NR 418

CN8A_HUMAN NIITPISLDDVPPRIARAMENEEYWDFDIFELEAATH---NR 512

CN8B_HUMAN HLAMPITINDVPPCISQLLDNEESWDFNIFELEAITH---KR 571

CN7A_HUMAN SNSLNILDDDYNGQAKCMLEKVGNWNFDIFLFDRLTN---GN 168

CN7B_HUMAN QAPLHLLDEDYLGQARHMLSKVGMWDFDIFLFDRLTN---GN 129

CN5A_HUMAN EETRELQSLAAAVVPSAQTLKITDFSFSDFELS------DL 569

CN11_HUMAN SKAEVDKFK-AANIPLVSELAIDDIHFDDFSLD------VD 675

CN6A_HUMAN KEPWECEEEELAEILQAELPDADKYEINKFHFSDLPLT--EL 515

CN6B_HUMAN KEPADCDEDELGEILKEELPGPTTFDIYEFHFSDLECT--EL 514

CN6C_HUMAN DVIDDCEEKQLVAILKEDLPDPRSAELYEFRFSDFPLT--EH 519

CN10_HUMAN SYHSICTSEEWQGLMQFTLPVRLCKEIELFHFDIGPF---EN 474

CN2A_HUMAN HMKVSDDEYTKLLHDGIQPVAAIDSNFASFTYTPRSLP--ED 613

CN9A_HUMAN TPRRDVPTYPKYLLSPETIEALRKPTFDVWLWE------PN 269

. :

PfPDE_alpha ISFNSFSNMHSLLSSKFQEHYNDIYDWNGNIENIY-----KA

PfPDE_beta KQIKKFLKQINISQLTKMIQFIDNKLLSDWDFNCLTY---FD

PfPDE_gamma DEFNVKKEMDMNLKCDNVNLDIWNTSFLNNETL------E

PfPDE_delta IAYEVEVLKNIKKINCDEIGKNWDYSFIDSEYG------KS

LmjPDE_LEISH IAVTPEEREAVMSIDFGGAYDFTSPGFNLFEVREKYS-EPMD

*h3********* *h4** *h5*********** *h6************

CN1A_HUMAN SLKFMIYELFTRYDLINRFKIPVSCLITFAEALEVGYSKYKNPYHNLIHAADVTQTVHYIM 234

CN1C_HUMAN ALKFIFYELLTRYDLISRFKIPISALVSFVEALEVGYSKHKNPYHNLMHAADVTQTVHYLL 244

CN1B_HUMAN ALRTIVFELLTRHNLISRFKIPTVFLMSFLDALETGYGKYKNPYHNQIHAADVTQTVHCFL 239

CN3A_HUMAN ILSQVSYRLFEDMGLFEAFKIPIREFMNYFHALEIGYR--DIPYHNRIHATDVLHAVWYLT 768

CN3B_HUMAN ILSQVMYTLFQDTGLLEIFKIPTQQFMNYFRALENGYR--DIPYHNRIHATDVLHAVWYLT 753

CN4A_HUMAN SLTCIMYMIFQERDLLKKFRIPVDTMVTYMLTLEDHYH-ADVAYHNSLHAADVLQSTHVLL 449

CN4B_HUMAN PLTCIMYAIFQERDLLKTFRISSDTFITYMMTLEDHYH-SDVAYHNSLHAADVAQSTHVLL 422

CN4C_HUMAN PLTAIIFSIFQERDLLKTFQIPADTLATYLLMLEGHYH-ANVAYHNSLHAADVAQSTHVLL 404

CN4D_HUMAN PLTVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYH-ADVAYHNNIHAADVVQSTHVLL 478

CN8A_HUMAN PLIYLGLKMFARFGICEFLHCSESTLRSWLQIIEANYH-SSNPYHNSTHSADVLHATAYFL 572

CN8B_HUMAN PLVYLGLKVFSRFGVCEFLNCSETTLRAWFQVIEANYH-SSNAYHNSTHAADVLHATAFFL 631

CN7A_HUMAN SLVSLTFHLFSLHGLIEYFHLDMMKLRRFLVMIQEDYH-SQNPYHNAVHAADVTQAMHCYL 228

CN7B_HUMAN SLVTLLCHLFNTHGLIHHFKLDMVTLHRFLVMVQEDYH-SQNPYHNAVHAADVTQAMHCYL 189

CN5A_HUMAN ETALCTIRMFTDLNLVQNFQMKHEVLCRWILSVKKNYRK-NVAYHNWRHAFNTAQCMFAAL 629

CN11_HUMAN AMITAALRMFMELGMVQKFKIDYETLCRWLLTVRKNYR--MVLYHNWRHAFNVCQLMFAML 734

CN6A_HUMAN ELVKCGIQMYYELKVVDKFHIPQEALVRFMYSLSKGYR--KITYHNWRHGFNVGQTMFSLL 574

CN6B_HUMAN DLVKCGIQMYYELGVVRKFQIPQEVLVRFLFSISKGYR--RITYHNWRHGFNVAQTMFTLL 573

CN6C_HUMAN GLIKCGIRLFFEINVVEKFKVPVEVLTRWMYTVRKGYR--AVTYHNWQHGFNVGQTMFTLL 578

CN10_HUMAN MWPGIFVYMVHRSCGTSCFEL--EKLCRFIMSVKKNYR--RVPYHNWKHAVTVAHCMYAIL 531

CN2A_HUMAN DTSMAILSMLQDMNFINNYKIDCPTLARFCLMVKKGYR--DPPYHNWMHAFSVSHFCYLLY 672

CN9A_HUMAN EMLSCLEHMYHDLGLVRDFSINPVTLRRWLFCVHDNYR--NNPFHNFRHCFCVAQMMYSMV 328

: : : : * :** * . :

AA A

PfPDE_alpha NTFISIGYKLLYPLGVLEANFDKEKLKKFLFRICSYYN--DIPYHTSLHAAQVAHFSKSML

PfPDE_beta ESEYPFFDINLSLICTIDHNIPINIIINFLCFVEKQYN--NVPYHNTIHATMVTQKFFCLA

PfPDE_gamma DIFIHIGNKLLKMYYTTNHNIPSETLYSLLYEMKNGYN--NVPYHNSIHAAMVTHHCNVLV

PfPDE_delta TLVILEVGYHLISPYIENNENKKKKLQLFLLLINSMYF--PNPYHNANHGATVCHLSKCLA

LmjPDE_LEISH AAAGVVYNLLWNSGLPEKFGCREQTLLNFILQCRRRYR--RVPYHNFYHVVDVCQTLHTYL

CN1A_HUMAN LHTG------IMHWLTELEILA 250

CN1C_HUMAN YKTG------VANWLTELEIFA 260

CN1B_HUMAN LRTG------MVHCLSEIELLA 255

CN3A_HUMAN TQPIPGLSTVINDHGSTSDSDSDSGFTHGHMGYVFSKTYNVTDDKYGCLSGNIPALELMA 828

CN3B_HUMAN TRPVPGLQQIHNGCGTGNETDSDGRINHGRIAYISSKSCSNPDESYGCLSSNIPALELMA 813

CN4A_HUMAN ATPA------LDAVFTDLEILA 465

CN4B_HUMAN STPA------LDAVFTDLEILA 438

CN4C_HUMAN ATPA------LEAVFTDLEILA 420

CN4D_HUMAN STPA------LEAVFTDLEILA 494

CN8A_HUMAN SKER------IKETLDPIDEVA 588

CN8B_HUMAN GKER------VKGSLDQLDEVA 647

CN7A_HUMAN KEPK------LANSVTPWDILL 244

CN7B_HUMAN KEPK------LASFLTPLDIML 205

CN5A_HUMAN KAGK------IQNKLTDLEILA 645

CN11_HUMAN TTAG------FQDILTEVEILA 750

CN6A_HUMAN VTGK------LKRYFTDLEALA 590

CN6B_HUMAN MTGK------LKSYYTDLEAFA 589

CN6C_HUMAN MTGR------LKKYYTDLEAFA 594

CN10_HUMAN QNNH------TLFTDLERKG 545

CN2A_HUMAN KNLE------LTNYLEDIEIFA 688

CN9A_HUMAN WLCS------LQEKFSQTDILI 344

:

PfPDE_alpha FMLD------MNHKISAIDEFC

PfPDE_beta KKLG------IYDDLEYKIKLV

PfPDE_gamma SNLN------TANILRDNELGA

PfPDE_delta HITD------YDSYLNNTYMIC

LmjPDE_LEISH YTGKASE------LLTELECYVLLV

*h7**** *h8**** *h9**** *h10*********

CN1A_HUMAN MVFAAAIHDYEHTGTTNNFHIQTRSDVAILYNDR---SVLENHHVSAAYRLMQE-EEMNILI 308

CN1C_HUMAN IIFSAAIHDYEHTGTTNNFHIQTRSDPAILYNDR---SVLENHHLSAAYRLLQDDEEMNILI 319

CN1B_HUMAN IIFAAAIHDYEHTGTTNSFHIQTKSECAIVYNDR---SVLENHHISSVFRLMQD-DEMNIFI 313

CN3A_HUMAN LYVAAAMHDYDHPGRTNAFLVATSAPQAVLYNDR---SVLENHHAAAAWNLFMSRPEYNFLI 887

CN3B_HUMAN LYVAAAMHDYDHPGRTNAFLVATNAPQAVLYNDR---SVLENHHAASAWNLYLSRPEYNFLL 872

CN4A_HUMAN ALFAAAIHDVDHPGVSNQFLINTNSELALMYNDE---SVLENHHLAVGFKLLQE-DNCDIFQ 523

CN4B_HUMAN AIFAAAIHDVDHPGVSNQFLINTNSELALMYNDE---SVLENHHLAVGFKLLQE-EHCDIFM 496

CN4C_HUMAN ALFASAIHDVDHPGVSNQFLINTNSELALMYNDA---SVLENHHLAVGFKLLQA-ENCDIFQ 478

CN4D_HUMAN AIFASAIHDVDHPGVSNQFLINTNSELALMYNDS---SVLENHHLAVGFKLLQE-ENCDIFQ 552

CN8A_HUMAN ALIAATIHDVDHPGRTNSFLCNAGSELAILYNDT---AVLESHHAALAFQLTTGDDKCNIFK 647

CN8B_HUMAN ALIAATVHDVDHPGRTNSFLCNAGSELAVLYNDT---AVLESHHTALAFQLTVKDTKCNIFK 706

CN7A_HUMAN SLIAAATHDLDHPGVNQPFLIKTNHYLATLYKNT---SVLENHHWRSAVGLLR---ESGLFS 300

CN7B_HUMAN GLLAAAAHDVDHPGVNQPFLIKTNHHLANLYQNM---SVLENHHWRSTIGMLR---ESRLLA 261

CN5A_HUMAN LLIAALSHDLDHRGVNNSYIQRSEHPLAQLYCH----SIMEHHHFDQCLMILNS-PGNQILS 702

CN11_HUMAN VIVGCLCHDLDHRGTNNAFQAKSGSALAQLYGTS---ATLEHHHFNHAVMILQS-EGHNIFA 808

CN6A_HUMAN MVTAAFCHDIDHRGTNNLYQMKSQNPLAKLHGS----SILERHHLEFGKTLLRD-ESLNIFQ 647

CN6B_HUMAN MVTAGLCHDIDHRGTNNLYQMKSQNPLAKLHGS----SILERHHLEFGKFLLSE-ETLNIYQ 646

CN6C_HUMAN MLAAAFCHDIDHRGTNNLYQMKSTSPLARLHGS----SILERHHLEYSKTLLQD-ESLNIFQ 651

CN10_HUMAN LLIACLCHDLDHRGFSNSYLQKFDHPLAALYST----STMEQHHFSQTVSILQL-EGHNIFS 602

CN2A_HUMAN LFISCMCHDLDHRGTNNSFQVASKSVLAALYSSEG--SVMERHHFAQAIAILNT-HGCNIFD 747

CN9A_HUMAN LMTAAICHDLDHPGYNNTYQINARTELAVRYNDI---SPLENHHCAVAFQILAE-PECNIFS 402

. ** :* * .: : * : : :* ** : :

AA A A

PfPDE_alpha LHISSLCHDTGHPGLNNYFLINSENNLALTYNDN---SVLENYHCSLLFKTLKN-PNYNIFE

PfPDE_beta MFISGICHDIGHPGYNNLFFVNSLHPLSIIYNDI---SVLENYHASITFKILQL-NQCNILK

PfPDE_gamma LFVASLGHDIGHFGRTNIFLKNCCNFLSIIYNDK---SILENYHCSYLFNILLK-DENNIFK

PfPDE_delta YLIASIAHDVGHPGKTNSYLSETNHILSIRYNDM---SILENYHCSITFSILQL-IGFDFLI

LmjPDE_LEISH LLVTALVHDLDHMGVNNSFYLKTDSPLGILSSASGNNSVLEVHHCSLAIEILSDPAADVFEG

*h11************* *h12**********

CN1A_HUMAN N------LSKDDWRDLRNLVIEMVLSTDMSGHFQQIKNIRNSLQQ------347

CN1C_HUMAN N------LSKDDWREFRTLVIEMVMATDMSCHFQQIKAMKTALQQ------358

CN1B_HUMAN N------LTKDEFVELRALVIEMVLATDMSCHFQQVKTMKTALQQ------352

CN3A_HUMAN N------LDHVEFKHFRFLVIEAILATDLKKHFDFVAKFNGKVNDDVGI------931

CN3B_HUMAN H------LDHVEFKRFRFLVIEAILATDLKKHFDFLAEFNAKANDVNSNGI------918

CN4A_HUMAN N------LSKRQRQSLRKMVIDMVLATDMSKHMTLLADLKTMVETKKVTSSG------572

CN4B_HUMAN N------LTKKQRQTLRKMVIDMVLATDMSKHMSLLADLKTMVETKKVTSSG------545

CN4C_HUMAN N------LSAKQRLSLRRMVIDMVLATDMSKHMNLLADLKTMVETKKVTSLG------527

CN4D_HUMAN N------LTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSG------601

CN8A_HUMAN N------MERNDYRTLRQGIIDMVLATEMTKHFEHVNKFVNSINKPLATLEENGETDKNQ 707

CN8B_HUMAN N------IDRNHYRTLRQAIIDMVLATEMTKHFEHVNKFVNSINKPM--AAEIEGSDCEC 762

CN7A_HUMAN H------LPLESRQQMETQIGALILATDISRQNEYLSLFRSHLDRG------343

CN7B_HUMAN H------LPKEMTQDIEQQLGSLILATDINRQNEFLTRLKAHLHNK------304

CN5A_HUMAN G------LSIEEYKTTLKIIKQAILATDLALYIKRRGEFFELIRKN------745

CN11_HUMAN N------LSSKEYSDLMQLLKQSILATDLTLYFERRTEFFELVSKG------851

CN6A_HUMAN N------LNRRQHEHAIHMMDIAIIATDLALYFKKRTMFQKIVDQSKTYESE------Q 700

CN6B_HUMAN N------LNRRQHEHVIHLMDIAIIATDLALYFKKRAMFQKIVDESKNYQDK------K 699

CN6C_HUMAN N------LNKRQFETVIHLFEVAIIATDLALYFKKRTMFQKIVDACEQMQTE------E 704

CN10_HUMAN T------LSSSEYEQVLEIIRKAIIATDLALYFGNRKQLEEMYQT------645

CN2A_HUMAN H------FSRKDYQRMLDLMRDIILATDLAHHLRIFKDLQKMAEV------789

CN9A_HUMAN N------IPPDGFKQIRQGMITLILATDMARHAEIMDSFKEKMEN------443

: . :::*:: :

A

PfPDE_alpha H------YPYHIFISCKKNIIKAILSTDMKNHFEYISDFRTSKEFIDYDNLS------

PfPDE_beta N------FSEKDFRMMRSYIIELILSTDMKHHFEIISKFRIRRENED------

PfPDE_gamma N------EDPKCLLALRQQIIELILATDMSKHIKILAQFRIKSIK------

PfPDE_delta NNEDTKLVEKNNYTNMRKFIIELIISTDMKLHFEYVDIFKKRKKS------

LmjPDE_LEISH ------LSGQDVAYAYRALIDCVLATDMAKHADALSRFTELATS------

*h13************ *h14********************

CN1A_HUMAN ------PEGIDRAKTMSLILHAADISHPAKSWKLHYRWTMALMEEFFLQGDKEAELG 403

CN1C_HUMAN ------PEAIEKPKALSLMLHTADISHPAKAWDLHHRWTMSLLEEFFRQGDREAELG 414

CN1B_HUMAN ------LERIDKPKALSLLLHAADISHPTKQWLVHSRWTKALMEEFFRQGDKEAELG 408

CN3A_HUMAN -----DWTNENDRLLVCQMCIKLADINGPAKCKELHLQWTDGIVNEFYEQGDEEASLG 988

CN3B_HUMAN -----EWSNENDRLLVCQVCIKLADINGPAKVRDLHLKWTEGIVNEFYEQGDEEANLG 975

CN4A_HUMAN ---VLLLDNYSDRIQVLRNMVHCADLSNPTKPLELYRQWTDRIMAEFFQQGDRERERG 629

CN4B_HUMAN ---VLLLDNYTDRIQVLRNMVHCADLSNPTKSLELYRQWTDRIMEEFFQQGDKERERG 602

CN4C_HUMAN ---VLLLDNYSDRIQVLQNLVHCADLSNPTKPLPLYRQWTDRIMAEFFQQGDRERESG 584

CN4D_HUMAN ---VLLLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERG 658

CN8A_HUMAN EVINTMLRTPENRTLIKRMLIKCADVSNPCRPLQYCIEWAARISEEYFSQTDEEKQQG 765

CN8B_HUMAN NPAG--KNFPENQILIKRMMIKCADVANPCRPLDLCIEWAGRISEEYFAQTDEEKRQG 820

CN7A_HUMAN ---DLCLEDTRHRHLVLQMALKCADICNPCRTWELSKQWSEKVTEEFFHQGDIEKKYH 400

CN7B_HUMAN ---DLRLEDAQDRHFMLQIALKCADICNPCRIWEMSKQWSERVCEEFYRQGELEQKFE 361

CN5A_HUMAN ---QFNLEDPHQKELFLAMLMTACDLSAITKPWPIQQRIAELVATEFFDQGDRERKEL 803

CN11_HUMAN ---EYDWNIKNHRDIFRSMLMTACDLGAVTKPWEISRQVAELVTSEFFEQGDRERLEL 909

CN6A_HUMAN EWTQYMMLEQTRKEIVMAMMMTACDLSAITKPWEVQSQVALLVAAEFWEQGDLERTVL 758

CN6B_HUMAN SWVEYLSLETTRKEIVMAMMMTACDLSAITKPWEVQSKVALLVAAEFWEQGDLERTVL 757

CN6C_HUMAN EAIKYVTVDPTKKEIIMAMMMTACDLSAITKPWEVQSQVALMVANEFWEQGDLERTVL 762

CN10_HUMAN --GSLNLNNQSHRDRVIGLMMTACDLCSVTKLWPVTKLTANDIYAEFWAEGDEMKKLG 702

CN2A_HUMAN ---GYDRNNKQHHRLLLCLLMTSCDLSDQTKGWKTTRKIAELIYKEFFSQGDLEKAMG 846

CN9A_HUMAN ----FDYSNEEHMTLLKMILIKCCDISNEVRPMEVAEPWVDCLLEEYFMQSDREKSEG 500

: .*: : : *:: : : .

A A

PfPDE_alpha ------NDQIWQIFCLILKASDIGHSTLEWNKHLEWTLKINEEFYLQGLLEKSLN

PfPDE_beta ---FDYIKNSDDLLILTKMIIKSADISHGSVSWSEHYCWCQRVLSEFYTQGDEELKNK

PfPDE_gamma ----IKSYIEKNIILCLKMIIKAADLSHNCVDWSEHYQWVKRLVNEFYYEGDELFQMG

PfPDE_delta ---QNFDISDTDAINLGTINIKLADIGHTCLKWKDHAKWTMLVSEEFFSQKRVEELHK

LmjPDE_LEISH ---GFEKDNDTHRRLVMETLIKAGDVSNVTKPFETSRMWAMAVTEEFYRQGDMEKEKG

CN1A_HUMAN ------LP 405

CN1C_HUMAN ------LP 416

CN1B_HUMAN ------LP 410

CN3A_HUMAN ------LP 990

CN3B_HUMAN ------LP 977

CN4A_HUMAN ------ME 631

CN4B_HUMAN ------ME 604

CN4C_HUMAN ------LD 586

CN4D_HUMAN ------ME 660

CN8A_HUMAN ------LP 767

CN8B_HUMAN ------LP 822

CN7A_HUMAN ------LG 402

CN7B_HUMAN ------LE 363

CN5A_HUMAN ------NI 805

CN11_HUMAN ------KL 911

CN6A_HUMAN ------QQ 760

CN6B_HUMAN ------DQ 759

CN6C_HUMAN ------QQ 764

CN10_HUMAN ------I 704

CN2A_HUMAN ------N 848

CN9A_HUMAN ------LP 502

PfPDE_alpha ------IQ

PfPDE_beta ------MP

PfPDE_gamma ------YK

PfPDE_delta NKNIDPLNFSNFGKEDNIDEGMIFNYENIYINYINNINNINTYDYSYIK

LmjPDE_LEISH ------VE

*h15a****** *h15b******

CN1A_HUMAN FS-PLCDRKST-MVAQSQIGFIDFIVEPTFSLLTDSTEKIVI 440

CN1C_HUMAN FS-PLCDRKST-MVAQSQVGFIDFIVEPTFTVLTDMTEKIVS 451

CN1B_HUMAN FS-PLCDRTST-LVAQSQIGFIDFIVEPTFSVLTDVAEKSVQ 446

CN3A_HUMAN IS-PFMDRSAP-QLANLQESFISHIVGPLCNSYDSAGLMPGK 1026

CN3B_HUMAN IS-PFMDRSSP-QLAKLQESFITHIVGPLCNSYDAAGLLPGQ 1012

CN4A_HUMAN IS-PMCDKHTA-SVEKSQVGFIDYIVHPLWETWADLVHPD-- 664

CN4B_HUMAN IS-PMCDKHTA-SVEKSQVGFIDYIVHPLWETWADLVQPD-- 637

CN4C_HUMAN IS-PMCDKHTA-SVEKSQVGFIDYIAHPLWETWADLVHPD-- 619

CN4D_HUMAN IS-PMCDKHNA-SVEKSQVGFIDYIVHPLWETWADLVHPD-- 693

CN8A_HUMAN VVMPVFDRNTC-SIPKSQISFIDYFITDMFDAWDAFVD---- 798

CN8B_HUMAN VVMPVFDRNTC-SIPKSQISFIDYFITDMFDAWDAFAH---- 853

CN7A_HUMAN VS-PLCDRHTE-SIANIQIGFMTYLVEPLFTEWARFS-NTRL 436

CN7B_HUMAN IS-PLCNQQKD-SIPSIQIGFMSYIVEPLFREWAHFTGNSTL 398

CN5A_HUMAN EPTDLMNREKKNKIPSMQVGFIDAICLQLYEALTHVSED--- 838

CN11_HUMAN TPSAIFDRNRKDELPRLQLEWIDSICMPLYQALVKVNVK--- 944

CN6A_HUMAN NPIPMMDRNKADELPKLQVGFIDFVCTFVYKEFSRFHEE--- 793

CN6B_HUMAN QPIPMMDRNKAAELPKLQVGFIDFVCTFVYKEFSRFHEE--- 792

CN6C_HUMAN QPIPMMDRNKRDELPKLQVGFIDFVCTFVYKEFSRFHKE--- 797

CN10_HUMAN QPIPMMDRDKKDEVPQGQLGFYNAVAIPCYTTLTQILPP--- 737

CN2A_HUMAN RPMEMMDREKA-YIPELQISFMEHIAMPIYKLLQDLFPK--- 880

CN9A_HUMAN VA-PFMDRDKV-TKATAQIGFIKFVLIPMFETVTKLFPMV-- 535

: * :

A

PfPDE_alpha NSFLCDINTMN-KLALSQIDFLKHLCIPLFNELNYICKNNDV

PfPDE_beta LS-PLCDRTKHNEVCKSQITFLKFVVMPLFEELSHIDNNKFI

PfPDE_gamma IN-PLFDRNCHNNFIQIQRTFLKELVYPLIISLKTLDNTSI-

PfPDE_delta LN-FIHHHDFVKSIPSTQVYFFEIIVMPLIKELQSMEKSKKE

LmjPDE_LEISH VL-PMFDRSKNNELARGQIGFIDFVAGKFFRDIVGNLFHGMQ

CN1A_HUMAN PLIEEASKAETSSYVASSSTTIVGLHIADALRRSNTKGSMSDGSYSPDYSLAAVDLKSF 499

CN1C_HUMAN PLIDETSQTGGTGQRRSSLNSISSSDAKRSGVKTSGSEGSAPINNSVISVDYKSF---- 506

CN1B_HUMAN PLADEDSKSKNQPSFQWRQPSLDVEVGDPNPDVVSF------482

CN3A_HUMAN WVEDSDESGDTDDPEEEEEEAPAPNEEETCENNESPKKKTFK-RRKI------1072

CN3B_HUMAN WLEAEEDN-DTESGDDEDGEE-LDTEDEEMENNLNPKPPRRKSRRRI------1057

CN4A_HUMAN ------

CN4B_HUMAN ------

CN4C_HUMAN ------

CN4D_HUMAN ------

CN8A_HUMAN ------

CN8B_HUMAN ------

CN7A_HUMAN ------

CN7B_HUMAN ------

CN5A_HUMAN ------

CN11_HUMAN ------

CN6A_HUMAN ------

CN6B_HUMAN ------

CN6C_HUMAN ------

CN10_HUMAN ------

CN2A_HUMAN ------

CN9A_HUMAN ------

PfPDE_alpha ------

PfPDE_beta ------

PfPDE_gamma ------

PfPDE_delta I------

LmjPDE_LEISH W------

*h16************

CN1A_HUMAN KNNLVDIIQQNKERWKELAAQEARTSSQKCE 530

CN1C_HUMAN KATWTEVVHINRERWRAKVPKEEKAKKEAEE 537

CN1B_HUMAN RSTWVKRIQENKQKWKERAASGITNQMSIDE 513

CN3A_HUMAN YCQITQHLLQNHKMWKKVIEEEQRLAGIENQ 1103

CN3B_HUMAN FCQLMHHLTENHKIWKEIVEEEEKCKADGNK 1088

CN4A_HUMAN AQEILDTLEDNRDWYYSAIRQSPSPPPEEES 695

CN4B_HUMAN AQDILDTLEDNRNWYQSMIPQSPSPPLDEQN 668

CN4C_HUMAN AQDLLDTLEDNREWYQSKIPRSPSDLTNPER 650

CN4D_HUMAN AQDILDTLEDNREWYQSTIPQSPSPAPDDPE 724

CN8A_HUMAN LPDLMQHLDNNFKYWKGLDEMKLRNLRPPPE 829

CN8B_HUMAN LPALMQHLADNYKHWKTLDDLKCKSLRLPSD 884

CN7A_HUMAN SQTMLGHVGLNKASWKGLQREQSSSEDTDAA 467

CN7B_HUMAN SENMLGHLAHNKAQWKSLLPRQHRSRGSSGS 429

CN5A_HUMAN CFPLLDGCRKNRQKWQALAEQQEKMLINGES 869

CN11_HUMAN LKPMLDSVATNRSKWEELHQKRLLASTASSS 975

CN6A_HUMAN ITPMLDGITNNRKEWKALADEYDAKMKVQEE 824

CN6B_HUMAN ILPMFDRLQNNRKEWKALADEYEAKVKALEE 823

CN6C_HUMAN ITPMLSGLQNNRVEWKSLADEYDAKMKVIEE 828

CN10_HUMAN TEPLLKACRDNLSQWEKVIRGEETATWISSP 768

CN2A_HUMAN AAELYERVASNGEHWTKVSHKFTIRGIPSNN 911

CN9A_HUMAN EEIMLQPLWESRDRYEELKRIDDAMKELQKK 566

:

PfPDE_alpha YTHCIQPIENNIERWESHKNDNQNLGLHEKY

PfPDE_beta KSFCLKRLNSNCIMWDTLMKEEKTIEVYDPA

PfPDE_gamma TQDMINNVKRNYSKWTKIEKCQIKKKKYLNE

PfPDE_delta TQKVLHNLNINLQTWRLIEKNINLFYNTEKM

LmjPDE_LEISH CVDTVNSNRAKWQEILDGRRDSIRSSIV---

The numbering scheme has been taken from the SwissProt database.

Helix numbering is intended as a guide and refers to the PDE4 structure 1PTW. Differences occur in overall structure between PDE isoforms such as helices 1, 8 and 9.

"*" indicates that the residues in that column are identical in all sequences in the alignment
":" indicates that conserved substitutions have been observed
"." indicates that semi-conserved substitutions are observed

"A" indicates that this residue is in the active site

The multiple sequence alignment was conducted using Clustal W (1.82) on the http://www.ebi.ac.uk/clustalw/ web site. Modifications to the Clustal W alignment were required at the start of the sequences shown here, between helices 2 and 3, and between helices 15 and 16. In some cases further manual changes to the alignment were needed to coincide with alignments observed in the crystal structures themselves.