PDE5A_HUMAN
ID PDE5A_HUMAN Reviewed; 875 AA.
AC O76074; A0AV69; A8K2C4; O75026; O75887; Q86UI0; Q86V66; Q9Y6Z6;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 2.
DT 03-AUG-2022, entry version 203.
DE RecName: Full=cGMP-specific 3',5'-cyclic phosphodiesterase {ECO:0000305};
DE EC=3.1.4.35 {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:9714779};
DE AltName: Full=cGMP-binding cGMP-specific phosphodiesterase;
DE Short=CGB-PDE;
GN Name=PDE5A {ECO:0000312|HGNC:HGNC:8784}; Synonyms=PDE5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS PDE5A1 AND PDE5A2), FUNCTION,
RP CATALYTIC ACTIVITY, AND VARIANT VAL-93.
RX PubMed=9714779; DOI=10.1016/s0378-1119(98)00303-5;
RA Loughney K., Hill T.R., Florio V.A., Uher L., Rosman G.J., Wolda S.L.,
RA Jones B.A., Howard M.L., McAllister-Lucas L.M., Sonnenburg W.K.,
RA Francis S.H., Corbin J.D., Beavo J.A., Ferguson K.;
RT "Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-
RT binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase.";
RL Gene 216:139-147(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM PDE5A1), AND VARIANT
RP VAL-93.
RC TISSUE=Lung, and Placenta;
RX PubMed=9716380; DOI=10.1046/j.1432-1327.1998.2550391.x;
RA Yanaka N., Kotera J., Ohtsuka A., Akatsuka H., Imai Y., Michibata H.,
RA Fujishige K., Kawai E., Takebayashi S., Okumura K., Omori K.;
RT "Expression, structure and chromosomal localization of the human cGMP-
RT binding cGMP-specific phosphodiesterase PDE5A gene.";
RL Eur. J. Biochem. 255:391-399(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A1), AND VARIANT VAL-93.
RC TISSUE=Prostate, and Skeletal muscle;
RX PubMed=9642111; DOI=10.1006/bbrc.1998.8769;
RA Stacey P., Rulten S., Dapling A., Phillips S.C.;
RT "Molecular cloning and expression of human cGMP-binding cGMP-specific
RT phosphodiesterase.";
RL Biochem. Biophys. Res. Commun. 247:249-254(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2), AND VARIANT VAL-93.
RC TISSUE=Lung;
RA Kotera J., Imai Y., Omori K.;
RT "Molecular cloning and characterization of human cGMP-specific
RT phosphodiesterase 5A2 cDNA.";
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE5A2).
RC TISSUE=Colon carcinoma;
RA Sopory S., Visweswariah S.S.;
RT "PDE5A splice variants in T84 cells.";
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1), AND VARIANT
RP VAL-93.
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM PDE5A1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 157-411.
RC TISSUE=Trabecular meshwork;
RX PubMed=10393044;
RA Zhou L., Thompson W.J., Potter D.E.;
RT "Multiple cyclic nucleotide phosphodiesterases in human trabecular meshwork
RT cells.";
RL Invest. Ophthalmol. Vis. Sci. 40:1745-1752(1999).
RN [10]
RP PHOSPHORYLATION BY PRKG1.
RX PubMed=11723116; DOI=10.1074/jbc.m106562200;
RA Rybalkin S.D., Rybalkina I.G., Feil R., Hofmann F., Beavo J.A.;
RT "Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in
RT smooth muscle cells.";
RL J. Biol. Chem. 277:3310-3317(2002).
RN [11]
RP FUNCTION.
RX PubMed=25799991; DOI=10.1038/nature14332;
RA Lee D.I., Zhu G., Sasaki T., Cho G.S., Hamdani N., Holewinski R., Jo S.H.,
RA Danner T., Zhang M., Rainer P.P., Bedja D., Kirk J.A., Ranek M.J.,
RA Dostmann W.R., Kwon C., Margulies K.B., Van Eyk J.E., Paulus W.J.,
RA Takimoto E., Kass D.A.;
RT "Phosphodiesterase 9A controls nitric-oxide-independent cGMP and
RT hypertrophic heart disease.";
RL Nature 519:472-476(2015).
RN [12] {ECO:0007744|PDB:1T9R, ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF}
RP X-RAY CRYSTALLOGRAPHY (1.30 ANGSTROMS) OF 534-858 IN COMPLEX WITH ZINC,
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ALA-767; GLN-775 AND TRP-853,
RP AND COFACTOR.
RX PubMed=15260978; DOI=10.1016/j.molcel.2004.07.005;
RA Zhang K.Y.J., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S.,
RA Hsieh D., Neiman J., West B.L., Zhang C., Milburn M.V., Kim S.-H.,
RA Schlessinger J., Bollag G.;
RT "A glutamine switch mechanism for nucleotide selectivity by
RT phosphodiesterases.";
RL Mol. Cell 15:279-286(2004).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 537-860 IN COMPLEX WITH ZINC;
RP MAGNESIUM AND THE INHIBITORS SILDENAFIL; TADALAFIL AND VARDENAFIL,
RP COFACTOR, AND ACTIVITY REGULATION.
RX PubMed=12955149; DOI=10.1038/nature01914;
RA Sung B.-J., Hwang K.Y., Jeon Y.H., Lee J.I., Heo Y.-S., Kim J.H., Moon J.,
RA Yoon J.M., Hyun Y.-L., Kim E., Eum S.J., Park S.-Y., Lee J.-O., Lee T.G.,
RA Ro S., Cho J.M.;
RT "Structure of the catalytic domain of human phosphodiesterase 5 with bound
RT drug molecules.";
RL Nature 425:98-102(2003).
CC -!- FUNCTION: Plays a role in signal transduction by regulating the
CC intracellular concentration of cyclic nucleotides. This
CC phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP
CC (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-
CC generated cGMP (PubMed:15489334). {ECO:0000269|PubMed:15489334,
CC ECO:0000269|PubMed:9714779}.
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:0000269|PubMed:15260978, ECO:0000269|PubMed:9714779};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958;
CC Evidence={ECO:0000305|PubMed:15260978};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:12955149, ECO:0000269|PubMed:15260978};
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:0000269|PubMed:12955149, ECO:0000269|PubMed:15260978};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:12955149};
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:0000269|PubMed:12955149};
CC -!- ACTIVITY REGULATION: Sildenafil (Viagra) is a highly selective and
CC potent inhibitor of PDE5A and is effective in the treatment of penile
CC erectile dysfunction. Also inhibited by zaprinast.
CC {ECO:0000269|PubMed:12955149}.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
CC 3',5'-cyclic GMP: step 1/1.
CC -!- INTERACTION:
CC O76074; Q13976: PRKG1; NbExp=4; IntAct=EBI-9023531, EBI-3952014;
CC O76074; Q9NZD8: SPG21; NbExp=3; IntAct=EBI-9023531, EBI-742688;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=PDE5A1;
CC IsoId=O76074-1; Sequence=Displayed;
CC Name=PDE5A2;
CC IsoId=O76074-2; Sequence=VSP_004591;
CC -!- TISSUE SPECIFICITY: Expressed in aortic smooth muscle cells, heart,
CC placenta, skeletal muscle and pancreas and, to a much lesser extent, in
CC brain, liver and lung.
CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two
CC putative divalent metal sites and an N-terminal regulatory domain which
CC contains two homologous allosteric cGMP-binding regions, A and B.
CC -!- PTM: Phosphorylation is regulated by binding of cGMP to the two
CC allosteric sites (By similarity). Phosphorylation by PRKG1 leads to its
CC activation. {ECO:0000250, ECO:0000269|PubMed:11723116}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC {ECO:0000305}.
CC -!- CAUTION: Was initially thought to act as a major regulator of cardiac
CC hypertrophy in myocytes and muscle and investigations have been made on
CC selective PDE5A inhibitors that could protect against cardiovascular
CC disease. However, while PDE5A regulates nitric-oxide-generated cGMP,
CC nitric oxide signaling is often depressed by heart disease, limiting
CC its effect. Moreover, clinical trial using PDE5A inhibitors were
CC disappointing. {ECO:0000269|PubMed:25799991}.
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DR EMBL; AF043731; AAC63967.1; -; mRNA.
DR EMBL; AF043732; AAC63968.1; -; mRNA.
DR EMBL; AB001635; BAA33372.2; -; Genomic_DNA.
DR EMBL; D89094; BAA28945.1; -; mRNA.
DR EMBL; AJ004865; CAA06170.1; -; mRNA.
DR EMBL; AB015656; BAA81667.1; -; mRNA.
DR EMBL; AY264918; AAP21809.1; -; mRNA.
DR EMBL; AK290189; BAF82878.1; -; mRNA.
DR EMBL; AC093752; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC080089; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC126233; AAI26234.1; -; mRNA.
DR EMBL; AY266363; AAP31235.1; -; mRNA.
DR CCDS; CCDS34055.1; -. [O76074-2]
DR CCDS; CCDS3713.1; -. [O76074-1]
DR PIR; JW0106; JW0106.
DR RefSeq; NP_001074.2; NM_001083.3. [O76074-1]
DR RefSeq; NP_236914.2; NM_033430.2. [O76074-2]
DR RefSeq; NP_246273.2; NM_033437.3.
DR PDB; 1RKP; X-ray; 2.05 A; A=535-860.
DR PDB; 1T9R; X-ray; 2.10 A; A=531-875.
DR PDB; 1T9S; X-ray; 2.00 A; A/B=534-858.
DR PDB; 1TBF; X-ray; 1.30 A; A=534-858.
DR PDB; 1UDT; X-ray; 2.30 A; A=537-860.
DR PDB; 1UDU; X-ray; 2.83 A; A/B=537-860.
DR PDB; 1UHO; X-ray; 2.50 A; A=537-860.
DR PDB; 1XOZ; X-ray; 1.37 A; A=534-875.
DR PDB; 1XP0; X-ray; 1.79 A; A=534-875.
DR PDB; 2CHM; X-ray; 1.60 A; A=534-656, A=682-858.
DR PDB; 2H40; X-ray; 1.85 A; A=535-860.
DR PDB; 2H42; X-ray; 2.30 A; A/B/C=535-860.
DR PDB; 2H44; X-ray; 1.80 A; A=535-860.
DR PDB; 2XSS; X-ray; 2.50 A; A/B=346-509.
DR PDB; 3B2R; X-ray; 2.07 A; A/B=535-860.
DR PDB; 3BJC; X-ray; 2.00 A; A=1-875.
DR PDB; 3HC8; X-ray; 1.79 A; A=536-657, A=682-858.
DR PDB; 3HDZ; X-ray; 1.80 A; A=536-657, A=682-858.
DR PDB; 3JWQ; X-ray; 2.87 A; A/B/C/D=535-786, A/B/C/D=827-860.
DR PDB; 3JWR; X-ray; 2.99 A; A/B=535-786, A/B=827-860.
DR PDB; 3LFV; X-ray; 2.80 A; A/B=98-518.
DR PDB; 3MF0; X-ray; 3.10 A; A/B=89-518.
DR PDB; 3SHY; X-ray; 2.65 A; A=535-860.
DR PDB; 3SHZ; X-ray; 2.45 A; A=535-860.
DR PDB; 3SIE; X-ray; 1.93 A; A/B=535-860.
DR PDB; 3TGE; X-ray; 1.96 A; A=534-656, A=682-858.
DR PDB; 3TGG; X-ray; 1.91 A; A=534-660, A=662-858.
DR PDB; 4G2W; X-ray; 2.28 A; A=535-860.
DR PDB; 4G2Y; X-ray; 2.40 A; A=535-860.
DR PDB; 4I9Z; X-ray; 2.08 A; A=535-860.
DR PDB; 4IA0; X-ray; 2.17 A; A=535-860.
DR PDB; 4MD6; X-ray; 2.00 A; A=535-860.
DR PDB; 4OEW; X-ray; 2.44 A; A=535-860.
DR PDB; 4OEX; X-ray; 2.14 A; A=535-860.
DR PDB; 5JO3; X-ray; 1.49 A; B=534-858.
DR PDB; 5ZZ2; X-ray; 2.60 A; A=535-860.
DR PDB; 6ACB; X-ray; 2.80 A; A=535-860.
DR PDB; 6IWI; X-ray; 2.15 A; A=535-860.
DR PDB; 6L6E; X-ray; 1.92 A; A=536-861.
DR PDB; 6VBI; X-ray; 2.30 A; A/B=535-859.
DR PDBsum; 1RKP; -.
DR PDBsum; 1T9R; -.
DR PDBsum; 1T9S; -.
DR PDBsum; 1TBF; -.
DR PDBsum; 1UDT; -.
DR PDBsum; 1UDU; -.
DR PDBsum; 1UHO; -.
DR PDBsum; 1XOZ; -.
DR PDBsum; 1XP0; -.
DR PDBsum; 2CHM; -.
DR PDBsum; 2H40; -.
DR PDBsum; 2H42; -.
DR PDBsum; 2H44; -.
DR PDBsum; 2XSS; -.
DR PDBsum; 3B2R; -.
DR PDBsum; 3BJC; -.
DR PDBsum; 3HC8; -.
DR PDBsum; 3HDZ; -.
DR PDBsum; 3JWQ; -.
DR PDBsum; 3JWR; -.
DR PDBsum; 3LFV; -.
DR PDBsum; 3MF0; -.
DR PDBsum; 3SHY; -.
DR PDBsum; 3SHZ; -.
DR PDBsum; 3SIE; -.
DR PDBsum; 3TGE; -.
DR PDBsum; 3TGG; -.
DR PDBsum; 4G2W; -.
DR PDBsum; 4G2Y; -.
DR PDBsum; 4I9Z; -.
DR PDBsum; 4IA0; -.
DR PDBsum; 4MD6; -.
DR PDBsum; 4OEW; -.
DR PDBsum; 4OEX; -.
DR PDBsum; 5JO3; -.
DR PDBsum; 5ZZ2; -.
DR PDBsum; 6ACB; -.
DR PDBsum; 6IWI; -.
DR PDBsum; 6L6E; -.
DR PDBsum; 6VBI; -.
DR AlphaFoldDB; O76074; -.
DR SMR; O76074; -.
DR BioGRID; 114205; 13.
DR DIP; DIP-46287N; -.
DR IntAct; O76074; 6.
DR STRING; 9606.ENSP00000347046; -.
DR BindingDB; O76074; -.
DR ChEMBL; CHEMBL1827; -.
DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DR DrugBank; DB08729; 5-ethoxy-4-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)thiophene-2-sulfonamide.
DR DrugBank; DB06237; Avanafil.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB00975; Dipyridamole.
DR DrugBank; DB06246; Exisulind.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB03597; gamma-Glutamyl[S-(2-iodobenzyl)cysteinyl]glycine.
DR DrugBank; DB01972; Guanosine-5'-Monophosphate.
DR DrugBank; DB09282; Molsidomine.
DR DrugBank; DB05415; OSI-461.
DR DrugBank; DB00203; Sildenafil.
DR DrugBank; DB00820; Tadalafil.
DR DrugBank; DB00277; Theophylline.
DR DrugBank; DB09283; Trapidil.
DR DrugBank; DB06267; Udenafil.
DR DrugBank; DB00862; Vardenafil.
DR DrugCentral; O76074; -.
DR GuidetoPHARMACOLOGY; 1304; -.
DR iPTMnet; O76074; -.
DR PhosphoSitePlus; O76074; -.
DR BioMuta; PDE5A; -.
DR EPD; O76074; -.
DR jPOST; O76074; -.
DR MassIVE; O76074; -.
DR MaxQB; O76074; -.
DR PaxDb; O76074; -.
DR PeptideAtlas; O76074; -.
DR PRIDE; O76074; -.
DR ProteomicsDB; 50374; -. [O76074-1]
DR ProteomicsDB; 50375; -. [O76074-2]
DR Antibodypedia; 1386; 184 antibodies from 36 providers.
DR DNASU; 8654; -.
DR Ensembl; ENST00000264805.9; ENSP00000264805.5; ENSG00000138735.16. [O76074-2]
DR Ensembl; ENST00000354960.8; ENSP00000347046.3; ENSG00000138735.16. [O76074-1]
DR GeneID; 8654; -.
DR KEGG; hsa:8654; -.
DR MANE-Select; ENST00000354960.8; ENSP00000347046.3; NM_001083.4; NP_001074.2.
DR UCSC; uc003idf.4; human. [O76074-1]
DR CTD; 8654; -.
DR DisGeNET; 8654; -.
DR GeneCards; PDE5A; -.
DR HGNC; HGNC:8784; PDE5A.
DR HPA; ENSG00000138735; Low tissue specificity.
DR MIM; 603310; gene.
DR neXtProt; NX_O76074; -.
DR OpenTargets; ENSG00000138735; -.
DR PharmGKB; PA33132; -.
DR VEuPathDB; HostDB:ENSG00000138735; -.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000155475; -.
DR OMA; RDAYKHE; -.
DR OrthoDB; 904682at2759; -.
DR PhylomeDB; O76074; -.
DR TreeFam; TF316499; -.
DR BRENDA; 3.1.4.35; 2681.
DR PathwayCommons; O76074; -.
DR Reactome; R-HSA-418457; cGMP effects.
DR Reactome; R-HSA-9013422; RHOBTB1 GTPase cycle.
DR SignaLink; O76074; -.
DR SIGNOR; O76074; -.
DR UniPathway; UPA00763; UER00748.
DR BioGRID-ORCS; 8654; 10 hits in 1073 CRISPR screens.
DR ChiTaRS; PDE5A; human.
DR EvolutionaryTrace; O76074; -.
DR GeneWiki; CGMP-specific_phosphodiesterase_type_5; -.
DR GenomeRNAi; 8654; -.
DR Pharos; O76074; Tclin.
DR PRO; PR:O76074; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O76074; protein.
DR Bgee; ENSG00000138735; Expressed in calcaneal tendon and 149 other tissues.
DR ExpressionAtlas; O76074; baseline and differential.
DR Genevisible; O76074; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0030553; F:cGMP binding; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046069; P:cGMP catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0055118; P:negative regulation of cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0048599; P:oocyte development; IEA:Ensembl.
DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0060282; P:positive regulation of oocyte development; IEA:Ensembl.
DR GO; GO:0010749; P:regulation of nitric oxide mediated signal transduction; IEA:Ensembl.
DR GO; GO:0055119; P:relaxation of cardiac muscle; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0042098; P:T cell proliferation; IEA:Ensembl.
DR CDD; cd00077; HDc; 1.
DR DisProt; DP01244; -.
DR Gene3D; 1.10.1300.10; -; 1.
DR Gene3D; 3.30.450.40; -; 2.
DR InterPro; IPR003018; GAF.
DR InterPro; IPR029016; GAF-like_dom_sf.
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; PF01590; GAF; 2.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SMART; SM00065; GAF; 2.
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; Allosteric enzyme; Alternative splicing; cGMP; cGMP-binding;
KW Hydrolase; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; Zinc.
FT CHAIN 1..875
FT /note="cGMP-specific 3',5'-cyclic phosphodiesterase"
FT /id="PRO_0000198823"
FT DOMAIN 164..314
FT /note="GAF 1"
FT DOMAIN 346..503
FT /note="GAF 2"
FT DOMAIN 536..860
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 78..102
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 7..27
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 78..99
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 613
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 617
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:12955149,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R,
FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF"
FT BINDING 653
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:12955149,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R,
FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF"
FT BINDING 654
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:12955149"
FT BINDING 654
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:12955149,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R,
FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF"
FT BINDING 764
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:12955149,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1T9R,
FT ECO:0007744|PDB:1T9S, ECO:0007744|PDB:1TBF"
FT BINDING 817
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000269|PubMed:12955149"
FT MOD_RES 102
FT /note="Phosphoserine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..49
FT /note="MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKA ->
FT MLPFGDK (in isoform PDE5A2)"
FT /evidence="ECO:0000303|PubMed:9714779, ECO:0000303|Ref.4,
FT ECO:0000303|Ref.5"
FT /id="VSP_004591"
FT VARIANT 93
FT /note="A -> V (in dbSNP:rs3733526)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:9642111, ECO:0000269|PubMed:9714779,
FT ECO:0000269|PubMed:9716380, ECO:0000269|Ref.4"
FT /id="VAR_027775"
FT VARIANT 181
FT /note="S -> A (in dbSNP:rs17051276)"
FT /id="VAR_027776"
FT MUTAGEN 767
FT /note="A->N: Changes substrate selectivity from cGMP-
FT specific to dual cAMP and cGMP binding and hydrolysis; when
FT associated with Y-775 and Y-853."
FT /evidence="ECO:0000269|PubMed:15260978"
FT MUTAGEN 775
FT /note="Q->Y: Changes substrate selectivity from cGMP-
FT specific to dual cAMP and cGMP binding and hydrolysis; when
FT associated with N-767 and Y-853."
FT /evidence="ECO:0000269|PubMed:15260978"
FT MUTAGEN 853
FT /note="W->Y: Changes substrate selectivity from cGMP-
FT specific to dual cAMP and cGMP binding and hydrolysis; when
FT associated with N-767 and Y-775."
FT /evidence="ECO:0000269|PubMed:15260978"
FT CONFLICT 159
FT /note="I -> V (in Ref. 9; AAP31235)"
FT /evidence="ECO:0000305"
FT CONFLICT 310
FT /note="C -> G (in Ref. 9; AAP31235)"
FT /evidence="ECO:0000305"
FT CONFLICT 381
FT /note="S -> F (in Ref. 9; AAP31235)"
FT /evidence="ECO:0000305"
FT CONFLICT 406
FT /note="K -> R (in Ref. 9; AAP31235)"
FT /evidence="ECO:0000305"
FT CONFLICT 642
FT /note="E -> G (in Ref. 4; BAA81667)"
FT /evidence="ECO:0000305"
FT HELIX 103..106
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 115..117
FT /evidence="ECO:0007829|PDB:3LFV"
FT TURN 118..120
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 121..124
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 148..160
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 165..177
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 182..192
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 198..205
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 208..210
FT /evidence="ECO:0007829|PDB:3MF0"
FT STRAND 213..218
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 221..224
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 228..236
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 240..243
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 245..247
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 254..259
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 266..272
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 278..287
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 299..340
FT /evidence="ECO:0007829|PDB:3LFV"
FT TURN 342..345
FT /evidence="ECO:0007829|PDB:3MF0"
FT HELIX 346..362
FT /evidence="ECO:0007829|PDB:2XSS"
FT STRAND 365..372
FT /evidence="ECO:0007829|PDB:2XSS"
FT STRAND 374..376
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 379..387
FT /evidence="ECO:0007829|PDB:2XSS"
FT TURN 388..390
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 391..393
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 400..403
FT /evidence="ECO:0007829|PDB:2XSS"
FT HELIX 407..409
FT /evidence="ECO:0007829|PDB:2XSS"
FT HELIX 410..418
FT /evidence="ECO:0007829|PDB:2XSS"
FT STRAND 422..425
FT /evidence="ECO:0007829|PDB:2XSS"
FT TURN 427..429
FT /evidence="ECO:0007829|PDB:2XSS"
FT STRAND 431..433
FT /evidence="ECO:0007829|PDB:3LFV"
FT STRAND 451..457
FT /evidence="ECO:0007829|PDB:2XSS"
FT STRAND 461..471
FT /evidence="ECO:0007829|PDB:2XSS"
FT TURN 476..478
FT /evidence="ECO:0007829|PDB:3LFV"
FT HELIX 486..506
FT /evidence="ECO:0007829|PDB:2XSS"
FT HELIX 535..545
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 551..554
FT /evidence="ECO:0007829|PDB:1TBF"
FT TURN 555..557
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 568..581
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 584..587
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 592..604
FT /evidence="ECO:0007829|PDB:1TBF"
FT TURN 606..608
FT /evidence="ECO:0007829|PDB:1T9R"
FT STRAND 610..614
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 615..630
FT /evidence="ECO:0007829|PDB:1TBF"
FT TURN 631..633
FT /evidence="ECO:0007829|PDB:1UHO"
FT HELIX 635..637
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 640..652
FT /evidence="ECO:0007829|PDB:1TBF"
FT TURN 653..656
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 662..667
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 671..675
FT /evidence="ECO:0007829|PDB:1TBF"
FT STRAND 677..679
FT /evidence="ECO:0007829|PDB:6L6E"
FT HELIX 680..694
FT /evidence="ECO:0007829|PDB:1TBF"
FT TURN 700..703
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 706..722
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 725..740
FT /evidence="ECO:0007829|PDB:1TBF"
FT STRAND 746..748
FT /evidence="ECO:0007829|PDB:1UDU"
FT HELIX 749..764
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 766..769
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 772..796
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 803..805
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 807..812
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 813..823
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 825..835
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 837..839
FT /evidence="ECO:0007829|PDB:1TBF"
FT HELIX 840..857
FT /evidence="ECO:0007829|PDB:1TBF"
SQ SEQUENCE 875 AA; 99985 MW; 9E30C6C182F13388 CRC64;
MERAGPSFGQ QRQQQQPQQQ KQQQRDQDSV EAWLDDHWDF TFSYFVRKAT REMVNAWFAE
RVHTIPVCKE GIRGHTESCS CPLQQSPRAD NSAPGTPTRK ISASEFDRPL RPIVVKDSEG
TVSFLSDSEK KEQMPLTPPR FDHDEGDQCS RLLELVKDIS SHLDVTALCH KIFLHIHGLI
SADRYSLFLV CEDSSNDKFL ISRLFDVAEG STLEEVSNNC IRLEWNKGIV GHVAALGEPL
NIKDAYEDPR FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE
KDFAAYLAFC GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI LKKIAATIIS
FMQVQKCTIF IVDEDCSDSF SSVFHMECEE LEKSSDTLTR EHDANKINYM YAQYVKNTME
PLNIPDVSKD KRFPWTTENT GNVNQQCIRS LLCTPIKNGK KNKVIGVCQL VNKMEENTGK
VKPFNRNDEQ FLEAFVIFCG LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL
QSLAAAVVPS AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCRWIL
SVKKNYRKNV AYHNWRHAFN TAQCMFAALK AGKIQNKLTD LEILALLIAA LSHDLDHRGV
NNSYIQRSEH PLAQLYCHSI MEHHHFDQCL MILNSPGNQI LSGLSIEEYK TTLKIIKQAI
LATDLALYIK RRGEFFELIR KNQFNLEDPH QKELFLAMLM TACDLSAITK PWPIQQRIAE
LVATEFFDQG DRERKELNIE PTDLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF
PLLDGCRKNR QKWQALAEQQ EKMLINGESG QAKRN
