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): The HD domain is found in a superfamily of enzymes with a predicted or known phosphohydrolase activity. These enzymes appear to be involved in the nucleic acid metabolism, signal transduction and possibly other functions in bacteria, archaea and eukaryotes. The fact that all the highly conserved residues in the HD superfamily are histidines or aspartates suggests that coordination of divalent cations is essential for the activity of these proteins (PUBMED:9868367). This domain is also found in eukaryotic 3',5'-cGMP phosphodiesterase (EC 3.1.4.17) (PDE), which is located in photoreceptor outer segments and it is light activated, playing a pivotal role in signal transduction. This profile/HMM does not detect HD homologues in bacterial glycine aminoacyl-tRNA synthetases (beta subunit).
• GO function: catalytic activity (GO:0003824)

There are 7376 HDc domains in 7296 proteins in SMART's nrdb database.

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

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)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the HDc domain.

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

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
63.24	map00230	Purine metabolism
21.08	map02020	Two-component system - General
8.39	map04914	Progesterone-mediated oocyte maturation
2.74	map00760	Nicotinate and nicotinamide metabolism
1.72	map00240	Pyrimidine metabolism
0.39	map00260	Glycine, serine and threonine metabolism
0.39	map00970	Aminoacyl-tRNA biosynthesis
0.24	map00530	Aminosugars metabolism
0.24	map00740	Riboflavin metabolism
0.24	map00730	Thiamine metabolism
0.24	map00051	Fructose and mannose metabolism
0.16	map00791	Atrazine degradation
0.08	map00350	Tyrosine metabolism
0.08	map00251	Glutamate metabolism
0.08	map00903	Limonene and pinene degradation
0.08	map00650	Butanoate metabolism
0.08	map00620	Pyruvate metabolism
0.08	map00624	1- and 2-Methylnaphthalene degradation
0.08	map00120	Bile acid biosynthesis
0.08	map00471	D-Glutamine and D-glutamate metabolism
0.08	map00330	Arginine and proline metabolism
0.08	map00460	Cyanoamino acid metabolism
0.08	map00632	Benzoate degradation via CoA ligation
0.08	map00362	Benzoate degradation via hydroxylation

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with HDc domain which could be assigned to a KEGG orthologous group, and not all proteins containing HDc domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of HDc domains in PDB

PDB code	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
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
3djb	Crystal structure of a hd-superfamily hydrolase (bt9727_1981) from bacillus thuringiensis, northeast structural genomics consortium target bur114
3dto
3dy8
3dyl
3dyn
3dyq
3dys
3ecm
3ecn
3g3n
3gw7
3hc1
3hc8
3hdz
3hqw
3hqy
3hqz
3hr1
3i8v
3iak
3ibj
3irh
3itm
3itu
3jwq
3jwr
3k4s
3kh1
3kkt

Links (links to other resources describing this domain)

• INTERPRO: IPR003607