SMART: HDc domain annotation

HDc Metal dependent phosphohydrolases with conserved 'HD' motif.

SMART accession number:	SM00471
Description:	Includes eukaryotic cyclic nucleotide phosphodiesterases (PDEc). This profile/HMM does not detect HD homologues in bacterial glycine aminoacyl-tRNA synthetases (beta subunit).
Interpro abstract (IPR003607):	This entry represents the HD domain, which is is found in a superfamily of enzymes with a predicted or known phosphohydrolase activity. It also represents a related phosphodiesterase (PDEase) domain that is found in eukaryotic 3',5'-cGMP phosphodiesterase (EC 3.1.4.17), which is located in photoreceptor outer segments and it is light activated, playing a pivotal role in signal transduction.
GO function:	catalytic activity (GO:0003824)
Family alignment:	View or

There are 16581 HDc domains in 16413 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
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This tree shows only several representative species. The complete taxonomic breakdown of all proteins with HDc domain is also avaliable.

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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Wolf YI, Aravind L, Grishin NV, Koonin EV
- Evolution of aminoacyl-tRNA synthetases--analysis of unique domain architectures and phylogenetic trees reveals a complex history of horizontal gene transfer events.
- Genome Res. 1999; 9: 689-710
- Display abstract
- Phylogenetic analysis of aminoacyl-tRNA synthetases (aaRSs) of all 20 specificities from completely sequenced bacterial, archaeal, and eukaryotic genomes reveals a complex evolutionary picture. Detailed examination of the domain architecture of aaRSs using sequence profile searches delineated a network of partially conserved domains that is even more elaborate than previously suspected. Several unexpected evolutionary connections were identified, including the apparent origin of the beta-subunit of bacterial GlyRS from the HD superfamily of hydrolases, a domain shared by bacterial AspRS and the B subunit of archaeal glutamyl-tRNA amidotransferases, and another previously undetected domain that is conserved in a subset of ThrRS, guanosine polyphosphate hydrolases and synthetases, and a family of GTPases. Comparison of domain architectures and multiple alignments resulted in the delineation of synapomorphies-shared derived characters, such as extra domains or inserts-for most of the aaRSs specificities. These synapomorphies partition sets of aaRSs with the same specificity into two or more distinct and apparently monophyletic groups. In conjunction with cluster analysis and a modification of the midpoint-rooting procedure, this partitioning was used to infer the likely root position in phylogenetic trees. The topologies of the resulting rooted trees for most of the aaRSs specificities are compatible with the evolutionary "standard model" whereby the earliest radiation event separated bacteria from the common ancestor of archaea and eukaryotes as opposed to the two other possible evolutionary scenarios for the three major divisions of life. For almost all aaRSs specificities, however, this simple scheme is confounded by displacement of some of the bacterial aaRSs by their eukaryotic or, less frequently, archaeal counterparts. Displacement of ancestral eukaryotic aaRS genes by bacterial ones, presumably of mitochondrial origin, was observed for three aaRSs. In contrast, there was no convincing evidence of displacement of archaeal aaRSs by bacterial ones. Displacement of aaRS genes by eukaryotic counterparts is most common among parasitic and symbiotic bacteria, particularly the spirochaetes, in which 10 of the 19 aaRSs seem to have been displaced by the respective eukaryotic genes and two by the archaeal counterpart. Unlike the primary radiation events between the three main divisions of life, that were readily traceable through the phylogenetic analysis of aaRSs, no consistent large-scale bacterial phylogeny could be established. In part, this may be due to additional gene displacement events among bacterial lineages. Argument is presented that, although lineage-specific gene loss might have contributed to the evolution of some of the aaRSs, this is not a viable alternative to horizontal gene transfer as the principal evolutionary phenomenon in this gene class.
- Aravind L, Koonin EV
- The HD domain defines a new superfamily of metal-dependent phosphohydrolases.
- Trends Biochem Sci. 1998; 23: 469-72
Disease (disease genes where sequence variants are found in this domain)

Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

Protein	Disease
Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta (P35913) (SMART)	OMIM:180072: Night blindness, congenital stationary, type 3 OMIM:163500: Retinitis pigmentosa, autosomal recessive

3D Structures of HDc domains in PDB

PDB code	Main view	Title
1f0j		Catalytic domain of human phosphodiesterase 4b2b
1mkd		Crystal structure of pde4d catalytic domain and zardaverine complex
1oyn		Crystal structure of pde4d2 in complex with (r,s)-rolipram
1ptw		The crystal structure of amp-bound pde4 suggests a mechanism for phosphodiesterase catalysis
1q9m		Three dimensional structures of pde4d in complex with roliprams and implication on inhibitor selectivity
1rkp		Crystal structure of pde5a1-ibmx
1ro6		Crystal structure of pde4b2b complexed with rolipram (r & s)
1ro9		Crystal structures of the catalytic domain of phosphodiesterase 4b2b complexed with 8-br-amp
1ror		Crystal structures of the catalytic domain of phosphodiesterase 4b2b complexed with amp
1so2		Catalytic domain of human phosphodiesterase 3b in complex with a dihydropyridazine inhibitor
1soj		Catalytic domain of human phosphodiesterase 3b in complex with ibmx
1t9r		Catalytic domain of human phosphodiesterase 5a
1t9s		Catalytic domain of human phosphodiesterase 5a in complex with gmp
1taz		Catalytic domain of human phosphodiesterase 1b
1tb5		Catalytic domain of human phosphodiesterase 4b in complex with amp
1tb7		Catalytic domain of human phosphodiesterase 4d in complex with amp
1tbb		Catalytic domain of human phosphodiesterase 4d in complex with rolipram
1tbf		Catalytic domain of human phosphodiesterase 5a in complex with sildenafil
1udt		Crystal structure of human phosphodiesterase 5 complexed with sildenafil(viagra)
1udu		Crystal structure of human phosphodiesterase 5 complexed with tadalafil(cialis)
1uho		Crystal structure of human phosphodiesterase 5 complexed with vardenafil(levitra)
1vj7		Crystal structure of the bifunctional catalytic fragment of relseq, the rela/spot homolog from streptococcus equisimilis.
1xlx		Catalytic domain of human phosphodiesterase 4b in complex with cilomilast
1xlz		Catalytic domain of human phosphodiesterase 4b in complex with filaminast
1xm4		Catalytic domain of human phosphodiesterase 4b in complex with piclamilast
1xm6		Catalytic domain of human phosphodiesterase 4b in complex with (r)-mesopram
1xmu		Catalytic domain of human phosphodiesterase 4b in complex with roflumilast
1xmy		Catalytic domain of human phosphodiesterase 4b in complex with (r)-rolipram
1xn0		Catalytic domain of human phosphodiesterase 4b in complex with (r,s)-rolipram
1xom		Catalytic domain of human phosphodiesterase 4d in complex with cilomilast
1xon		Catalytic domain of human phosphodiesterase 4d in complex with piclamilast
1xoq		Catalytic domain of human phosphodiesterase 4d in complex with roflumilast
1xor		Catalytic domain of human phosphodiesterase 4d in complex with zardaverine
1xos		Catalytic domain of human phosphodiesterase 4b in complex with sildenafil
1xot		Catalytic domain of human phosphodiesterase 4b in complex with vardenafil
1xoz		Catalytic domain of human phosphodiesterase 5a in complex with tadalafil
1xp0		Catalytic domain of human phosphodiesterase 5a in complex with vardenafil
1xx7		Conserved hypothetical protein from pyrococcus furiosus pfu- 403030-001
1y2b		Catalytic domain of human phosphodiesterase 4d in complex with 3,5-dimethyl-1h-pyrazole-4-carboxylic acid ethyl ester
1y2c		Catalytic domain of human phosphodiesterase 4d in complex with 3,5-dimethyl-1-phenyl-1h-pyrazole-4-carboxylic acid ethyl ester
1y2d		Catalytic domain of human phosphodiesterase 4d in complex with 1-(4-methoxy-phenyl)-3,5-dimethyl-1h-pyrazole-4- carboxylic acid ethyl ester
1y2e		Catalytic domain of human phosphodiesterase 4d in complex with 1-(4-amino-phenyl)-3,5-dimethyl-1h-pyrazole-4- carboxylic acid ethyl ester
1y2h		Catalytic domain of human phosphodiesterase 4b in complex with 1-(2-chloro-phenyl)-3,5-dimethyl-1h-pyrazole-4- carboxylic acid ethyl ester
1y2j		Catalytic domain of human phosphodiesterase 4b in complex with 3,5-dimethyl-1-(3-nitro-phenyl)-1h-pyrazole-4- carboxylic acid ethyl ester
1y2k		Catalytic domain of human phosphodiesterase 4d in complex with 3,5-dimethyl-1-(3-nitro-phenyl)-1h-pyrazole-4- carboxylic acid ethyl ester
1ynb		Crystal structure of genomics apc5600
1yoy		Predicted coding region af1432 from archaeoglobus fulgidus
1z1l		The crystal structure of the phosphodiesterase 2a catalytic domain
1zkl		Multiple determinants for inhibitor selectivity of cyclic nucleotide phosphodiesterases
1zkn		Structure of pde4d2-ibmx
2chm		Crystal structure of n2 substituted pyrazolo pyrimidinones- a flipped binding mode in pde5
2cqz		Crystal structure of ph0347 protein from pyrococcus horikoshii ot3
2dqb		Crystal structure of dntp triphosphohydrolase from thermus thermophilus hb8, which is homologous to dgtp triphosphohydrolase
2fm0		Crystal structure of pde4d in complex with l-869298
2fm5		Crystal structure of pde4d2 in complex with inhibitor l-
2h40		Crystal structure of the catalytic domain of unliganded pde5
2h42		Crystal structure of pde5 in complex with sildenafil
2h44		Crystal structure of pde5a1 in complex with icarisid ii
2hd1		Crystal structure of pde9 in complex with ibmx
2hek		Crystal structure of o67745, a hypothetical protein from aquifex aeolicus at 2.0 a resolution.
2o08		Crystal structure of a putative hd superfamily hydrolase (np_242193.1) from bacillus halodurans at 1.90 a resolution
2o6i		Structure of an enterococcus faecalis hd domain phosphohydrolase
2o8h		Crystal structure of the catalytic domain of rat phosphodiesterase 10a
2ogi		Crystal structure of a putative metal dependent phosphohydrolase (np_688652.1) from streptococcus agalactiae 2603 at 1.85 a resolution
2oun		Crystal structure of pde10a2 in complex with amp
2oup		Crystal structure of pde10a
2ouq		Crystal structure of pde10a2 in complex with gmp
2our		Crystal structure of pde10a2 mutant d674a in complex with camp
2ous		Crystal structure of pde10a2 mutant d674a
2ouu		Crystal structure of pde10a2 mutant d674a in complex with cgmp
2ouv		Crystal structure of pde10a2 mutant of d564n
2ouy		Crystal structure of pde10a2 mutant d564a in complex with camp.
2ovv		Crystal structure of the catalytic domain of rat phosphodiesterase 10a
2ovy		Crystal structure of the catalytic domain of rat phosphodiesterase 10a
2paq		Crystal structure of the 5'-deoxynucleotidase yfbr
2par		Crystal structure of the 5'-deoxynucleotidase yfbr mutant e72a complexed with co(2+) and tmp
2pau		Crystal structure of the 5'-deoxynucleotidase yfbr mutant e72a complexed with co(2+) and damp
2pgs		Crystal structure of a putative deoxyguanosinetriphosphate triphosphohydrolase from pseudomonas syringae pv. phaseolicola 1448a
2pjq		Crystal structure of q88u62_lacpl from lactobacillus plantarum. northeast structural genomics target lpr71
2pq7		Crystal structure of predicted hd superfamily hydrolase (104161995) from uncultured thermotogales bacterium at 1.45 a resolution
2pw3		Structure of the pde4d-camp complex
2q14		Crystal structure of phosphohydrolase (bt4208) from bacteroides thetaiotaomicron vpi-5482 at 2.20 a resolution
2qgs		Crystal structure of se1688 protein from staphylococcus epidermidis. northeast structural genomics consortium target ser89
2qyk		Crystal structure of pde4a10 in complex with inhibitor npv
2qyl		Crystal structure of pde4b2b in complex with inhibitor npv
2qym		Crystal structure of unliganded pde4c2
2qyn		Crystal structure of pde4d2 in complex with inhibitor npv
2r8q		Structure of lmjpdeb1 in complex with ibmx
2wey		Human pde-papaverine complex obtained by ligand soaking of cross-linked protein crystals
2yy2		Crystal structure of the human phosphodiesterase 9a catalytic domain complexed with ibmx
3b2r		Crystal structure of pde5a1 catalytic domain in complex with vardenafil
3b57		Crystal structure of the lin1889 protein (q92an1) from listeria innocua. northeast structural consortium target lkr65
3bg2		Crystal structure of deoxyguanosinetriphosphate triphosphohydrolase from flavobacterium sp. med217
3bjc		Crystal structure of the pde5a catalytic domain in complex with a novel inhibitor
3ccg		Crystal structure of predicted hd superfamily hydrolase involved in nad metabolism (np_347894.1) from clostridium acetobutylicum at 1.50 a resolution
3d3p		Crystal structure of pde4b catalytic domain in complex with a pyrazolopyridine inhibitor
3djb		Crystal structure of a hd-superfamily hydrolase (bt9727_1981) from bacillus thuringiensis, northeast structural genomics consortium target bur114
3dto		Crystal structure of the metal-dependent hd domain- containing hydrolase bh2835 from bacillus halodurans, northeast structural genomics consortium target bhr130.
3dy8		Human phosphodiesterase 9 in complex with product 5'-gmp (e+p complex)
3dyl		Human phosphdiesterase 9 substrate complex (es complex)
3dyn		Human phosphodiestrase 9 in complex with cgmp (zn inhibited)
3dyq		Human phosphodiestrase 9 (inhibited by omitting divalent cation) in complex with cgmp
3dys		Human phosphodiestrase-5'gmp complex (ep), produced by soaking with 20mm cgmp+20 mm mncl2+20 mm mgcl2 for 2 hours, and flash-cooled to liquid nitrogen temperature when substrate was still abudant.
3ecm		Crystal structure of the unliganded pde8a catalytic domain
3ecn		Crystal structure of pde8a catalytic domain in complex with ibmx
3g3n		Pde7a catalytic domain in complex with 3-(2,6- difluorophenyl)-2-(methylthio)quinazolin-4(3h)-one
3gw7		Crystal structure of a metal-dependent phosphohydrolase with conserved hd domain (yedj) from escherichia coli in complex with nickel ions. northeast structural genomics consortium target er63
3hc1		Crystal structure of hdod domain protein with unknown function (np_953345.1) from geobacter sulfurreducens at 1.90 a resolution
3hc8		Investigation of aminopyridiopyrazinones as pde5 inhibitors: evaluation of modifications to the central ring system.
3hdz		Identification, synthesis, and sar of amino substituted pyrido[3,2b]pryaziones as potent and selective pde5 inhibitors
3hqw		Discovery of novel inhibitors of pde10a
3hqy		Discovery of novel inhibitors of pde10a
3hqz		Discovery of novel inhibitors of pde10a
3hr1		Discovery of novel inhibitors of pde10a
3i8v		Crystal structure of human pde4a with 4-(3-butoxy-4- methoxyphenyl)methyl-2-imidazolidone
3iak		Crystal structure of human phosphodiesterase 4d (pde4d) with papaverine.
3ibj		X-ray structure of pde2a
3irh		Structure of an enterococcus faecalis hd-domain protein complexed with dgtp and datp
3itm		Catalytic domain of hpde2a
3itu		Hpde2a catalytic domain complexed with ibmx
3jwq		Crystal structure of chimeric pde5/pde6 catalytic domain complexed with sildenafil
3jwr		Crystal structure of chimeric pde5/pde6 catalytic domain complexed with 3-isobutyl-1-methylxanthine (ibmx) and pde6 gamma-subunit inhibitory peptide 70-87.
3k4s		The structure of the catalytic domain of human pde4d with 4- (3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone
3kh1		Crystal structure of predicted metal-dependent phosphohydrolase (zp_00055740.2) from magnetospirillum magnetotacticum ms-1 at 1.37 a resolution
3kkt		Crystal structure of human pde4b with 5-[3-[(1s,2s,4r)- bicyclo[2.2.1]hept-2-yloxy]-4-methoxyp henyl]tetrahydro- 2(1h)-pyrimidinone reveals ordering of the c-terminal helix residues 502-509.

Links (links to other resources describing this domain)
INTERPRO IPR003607