PDE9A_PANTR
ID PDE9A_PANTR Reviewed; 593 AA.
AC H2QL32; K7AGW3;
DT 27-MAY-2015, integrated into UniProtKB/Swiss-Prot.
DT 21-MAR-2012, sequence version 1.
DT 03-AUG-2022, entry version 61.
DE RecName: Full=High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305};
DE EC=3.1.4.35 {ECO:0000250|UniProtKB:O76083};
GN Name=PDE9A;
OS Pan troglodytes (Chimpanzee).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9598;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16136131; DOI=10.1038/nature04072;
RG Chimpanzee sequencing and analysis consortium;
RT "Initial sequence of the chimpanzee genome and comparison with the human
RT genome.";
RL Nature 437:69-87(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Maudhoo M.D., Meehan D.T., Norgren R.B. Jr.;
RT "De novo assembly of the reference chimpanzee transcriptome from NextGen
RT mRNA sequences.";
RL Submitted (OCT-2012) to the EMBL/GenBank/DDBJ databases.
RN [3] {ECO:0007744|PDB:4QGE}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH ZINC; MAGNESIUM AND
RP INHIBITOR 3R, AND ACTIVITY REGULATION.
RX PubMed=25432025; DOI=10.1021/jm500836h;
RA Shao Y.X., Huang M., Cui W., Feng L.J., Wu Y., Cai Y., Li Z., Zhu X.,
RA Liu P., Wan Y., Ke H., Luo H.B.;
RT "Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic
RT agent.";
RL J. Med. Chem. 57:10304-10313(2014).
CC -!- FUNCTION: Specifically hydrolyzes the second messenger cGMP, which is a
CC key regulator of many important physiological processes. Highly
CC specific: compared to other members of the cyclic nucleotide
CC phosphodiesterase family, has the highest affinity and selectivity for
CC cGMP. Specifically regulates natriuretic-peptide-dependent cGMP
CC signaling in heart, acting as a regulator of cardiac hypertrophy in
CC myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in
CC heart. Additional experiments are required to confirm whether its
CC ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to
CC heart or is a general feature of the protein. In brain, involved in
CC cognitive function, such as learning and long-term memory.
CC {ECO:0000250|UniProtKB:O76083, ECO:0000250|UniProtKB:Q8QZV1}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746,
CC ChEBI:CHEBI:58115; EC=3.1.4.35;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per
CC subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Tightly binds zinc.
CC {ECO:0000250|UniProtKB:O76083};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:O76083};
CC Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations
CC per subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Binds magnesium less tightly than zinc.
CC {ECO:0000250|UniProtKB:O76083};
CC -!- ACTIVITY REGULATION: Specifically inhibited by a compound named 3r
CC ((R)-2-((1-cyclopentyl-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-
CC 6- yl)amino)-N-(4-methoxyphenyl)propanamide); the inhibitor forms a
CC hydrogen bond with Tyr-484, Ala-512 and Gln-513.
CC {ECO:0000269|PubMed:25432025}.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
CC 3',5'-cyclic GMP: step 1/1.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O76083}.
CC -!- SUBCELLULAR LOCATION: Cell projection, ruffle membrane
CC {ECO:0000250|UniProtKB:O76083}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:O76083}. Golgi apparatus
CC {ECO:0000250|UniProtKB:O76083}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:O76083}. Cell membrane, sarcolemma
CC {ECO:0000250|UniProtKB:O76083}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=H2QL32-1; Sequence=Displayed;
CC Name=2;
CC IsoId=H2QL32-2; Sequence=VSP_057676;
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE9 subfamily. {ECO:0000305}.
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DR EMBL; BS000229; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BS000230; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; GABC01010554; JAA00784.1; -; mRNA.
DR PDB; 4QGE; X-ray; 2.00 A; A/B=1-593.
DR PDBsum; 4QGE; -.
DR AlphaFoldDB; H2QL32; -.
DR SMR; H2QL32; -.
DR STRING; 9598.ENSPTRP00000024002; -.
DR PaxDb; H2QL32; -.
DR eggNOG; KOG3689; Eukaryota.
DR HOGENOM; CLU_032104_1_0_1; -.
DR InParanoid; H2QL32; -.
DR OrthoDB; 904682at2759; -.
DR TreeFam; TF314638; -.
DR UniPathway; UPA00763; UER00748.
DR Proteomes; UP000002277; Unplaced.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042383; C:sarcolemma; ISS:UniProtKB.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISS:UniProtKB.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046069; P:cGMP catabolic process; ISS:UniProtKB.
DR GO; GO:0046068; P:cGMP metabolic process; ISS:UniProtKB.
DR GO; GO:0019934; P:cGMP-mediated signaling; IBA:GO_Central.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00077; HDc; 1.
DR Gene3D; 1.10.1300.10; -; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR023088; PDEase.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SMART; SM00471; HDc; 1.
DR PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; cGMP;
KW Cytoplasm; Endoplasmic reticulum; Golgi apparatus; Hydrolase; Magnesium;
KW Membrane; Metal-binding; Phosphoprotein; Reference proteome; Zinc.
FT CHAIN 1..593
FT /note="High affinity cGMP-specific 3',5'-cyclic
FT phosphodiesterase 9A"
FT /id="PRO_0000433156"
FT DOMAIN 236..557
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 87..142
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 564..593
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 96..127
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 572..593
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 312
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 312..316
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 316
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25432025,
FT ECO:0007744|PDB:4QGE"
FT BINDING 352
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25432025,
FT ECO:0007744|PDB:4QGE"
FT BINDING 353
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 353
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25432025,
FT ECO:0007744|PDB:4QGE"
FT BINDING 353
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25432025,
FT ECO:0007744|PDB:4QGE"
FT BINDING 462
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 462
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25432025,
FT ECO:0007744|PDB:4QGE"
FT BINDING 484
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 512..513
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT MOD_RES 379
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8QZV1"
FT VAR_SEQ 88..147
FT /note="Missing (in isoform 2)"
FT /id="VSP_057676"
FT HELIX 250..255
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 263..265
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 268..281
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 284..287
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 292..304
FT /evidence="ECO:0007829|PDB:4QGE"
FT STRAND 310..313
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 314..330
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 333..335
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 339..351
FT /evidence="ECO:0007829|PDB:4QGE"
FT TURN 352..355
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 361..366
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 370..374
FT /evidence="ECO:0007829|PDB:4QGE"
FT TURN 375..377
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 380..394
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 396..398
FT /evidence="ECO:0007829|PDB:4QGE"
FT TURN 400..403
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 406..421
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 425..427
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 428..438
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 439..441
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 447..462
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 465..467
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 470..492
FT /evidence="ECO:0007829|PDB:4QGE"
FT TURN 493..495
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 500..502
FT /evidence="ECO:0007829|PDB:4QGE"
FT TURN 504..506
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 509..519
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 521..531
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 534..538
FT /evidence="ECO:0007829|PDB:4QGE"
FT HELIX 540..562
FT /evidence="ECO:0007829|PDB:4QGE"
SQ SEQUENCE 593 AA; 68449 MW; A3235CB335EC82C7 CRC64;
MGSGSSSYRP KAIYLDIDGR IQKVIFSKYC NSSDIMDLFC IATGLPRNTT ISLLTTDDAM
VSIDPTMPAN SERTPYKVRP VAIKQLSAGV EDKRTTSRGQ SAERPLRDRR VVGLEQPRRE
GAFESGQVEP RPREPQGCCQ EGQRIPPERE ELIQSVLAQV AEQFSRAFKI NELKAEVANH
LAVLEKRVEL EGLKVVEIEK CKSDIKKMRE ELAARSSRTN CPCKYSFLDN HKKLTPRRDV
PTYPKYLLSP ETIEALRKPT FDVWLWEPNE MLSCLEHMYH DLGLVRDFSI NPVTLRRWLF
CVHDNYRNNP FHNFRHCFCV AQMMYSMVWL CSLQENFSQM DILILMTAAI CHDLDHPGYN
NTYQINARTE LAVRYNDISP LENHHCAVAF QILAEPECNI FSNIPPDGFK QIRQGMITLI
LATDMARHAE IMDSFKEKME NFDYSNEEHM TLLKMILIKC CDISNEVRPM EVAEPWVDCL
LEEYFMQSDR EKSEGLPVAP FMDRDKVTKA TAQIGFIKFV LIPMFETVTK LFPMVEEIML
QPLWESRDRY EELKRIDDAM KELQKKTDSL TSGATEKSRE RSRDVKNSEG DCA
