CDD: a Conserved Domain Database for the
functional annotation of proteins
Aron Marchler-Bauer*, Shennan Lu, John B. Anderson, Farideh Chitsaz,
Myra K. Derbyshire, Carol DeWeese-Scott, Jessica H. Fong, Lewis Y. Geer,
Renata C. Geer, Noreen R. Gonzales, Marc Gwadz, David I. Hurwitz, John D. Jackson,
Zhaoxi Ke, Christopher J. Lanczycki, Fu Lu, Gabriele H. Marchler, Mikhail Mullokandov,
Marina V. Omelchenko, Cynthia L. Robertson, James S. Song, Narmada Thanki,
Roxanne A. Yamashita, Dachuan Zhang, Naigong Zhang, Chanjuan Zheng and
Stephen H. Bryant
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health,
Bldg. 38 A, Room 8N805, 8600 Rockville Pike, Bethesda, MD 20894, USA
Received September 29, 2010; Revised October 30, 2010; Accepted November 4, 2010
NCBI’s Conserved Domain Database (CDD) is a
resource for the annotation of protein sequences
with the location of conserved domain footprints,
and functional sites inferred from these footprints.
CDD includes manually curated domain models
that make use of protein 3D structure to refine
domain models and provide insights into sequence/
structure/function relationships. Manually curated
models are organized hierarchically if they describe
domain families that are clearly related by common
descent. As CDD also imports domain family models
from a variety of external sources, it is a partially re-
dundant collection. To simplify protein annotation,
redundant models and models describing homolo-
gous families are clustered into superfamilies. By
default, domain footprints are annotated with the
corresponding superfamily designation, on top of
high-confidence assignment of family membership.
Pre-computed domain annotation is available for
proteins in the Entrez/Protein dataset, and a novel
interface, Batch CD-Search, allows the computation
and download of annotation for large sets of protein
queries. CDD can be accessed via http://www.ncbi.
The annotation of protein sequences with the location of
domains is a common practice in the analysis of sequence
data. The identification of a conserved domain footprint
may be the only clue towards cellular or molecular
function of a protein, as it indicates local or partial simi-
larity to other proteins, some of which may have been
characterized experimentally. Furthermore, the study of
domain architectures in multi-domain protein families
often reveals their evolutionary history and is a common
tool in sequence classification. To this end, we released the
first version of Conserved Domain Database (CDD) to
the public in August 2000, >10 years ago, as a collection
of 2738 multiple sequence alignment models, based on the
content of the Pfam and SMART databases, and derived
database search tools to support the rapid computation of
sequence annotation. Since then, CDD has grown signifi-
cantly both in volume and in scope. CDD now imports
domain and protein family alignment models from Pfam
(1) (currently mirroring version 24), SMART (2), COG
(3), TIGRFAM (4) and the NCBI Protein Clusters
database (5). It also contains a set of models curated by
NCBI, many of which are organized into explicit
hierarchies of homologous domain families that reflect
processes. In addition, NCBI-curated domain models use
3D structure information explicitly, to define domain
boundaries, guide multiple sequence alignment and
provide insights into the relationship between sequence
conservation and molecular function.
CDD is updated several times a year, with occasional
updates initiated by new versions of imported data sets,
and with most incremental updates reflecting additions to
the NCBI-curated set of models. The current version of
CDD, v2.25, contains 37632 alignment models, of which
6056 have been curated by NCBI. Various aspects of CDD
have been highlighted in earlier manuscripts (6); here we
*To whom correspondence should be addressed. Tel: +1 301 435 4919; Fax: +1 301 435 7793; Email: email@example.com
Published online 24 November 2010Nucleic Acids Research, 2011, Vol. 39, Database issueD225–D229
? The Author(s) 2010. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
give a brief summary of major functionality pertaining to
sequence annotation, some of which has been presented in
greater detail in previous descriptions of CDD, and we
introduce a novel tool, Batch CD-Search, that facilitates
computation ofannotation forlarge sets ofprotein queries.
SPECIFIC HITS, DOMAIN SUPERFAMILIES AND
CDD is one of the many databases in NCBI’s Entrez query
and retrieval system and can be searched, using the
common Entrez interface, for keywords and terms
indexed from names, titles and descriptions of the
records. CDD is cross-linked with other databases such as
Entrez Protein, PubMed and NCBI BioSystems, to name a
few. However, most users of CDD encounter CDD records
by following Conserved Domains links from Entrez/
Protein sequence records, and also while executing
protein BLAST and PSI-BLAST searches via NCBI’s
web BLAST interface. The conserved domain model
database can be scanned quickly with protein queries,
and results showing domain annotation may already be
available, while BLAST continues to scan the significantly
larger non-redundant protein database. The application
that visualizes live or pre-computed search results has
been termed CD-Search (7), and the underlying algorithm
is Reverse Position-Specific BLAST (RPS-BLAST), a vari-
ation of the commonly used PSI-BLAST method (8,9).
Figure 1 illustrates the layout of a page reporting
conserved domain annotation. Live searches against the
CDD will reproduce pre-computed search results unless
the search parameters are modified from their default
settings. Detailed descriptions of search result pages have
been given previously (6). A concise domain annotation, as
shown by default, will provide the locations of top-scoring
domain footprints plus the locations of functional sites,
which can be derived from the domain footprints. The lo-
cations are shown graphically, and detailed alignments are
available as an option. Both CDD and CD-Search come
withup-do-date help documentation
formatting and interpretation of output in detail, and
which has been revised thoroughly in the past year.
Domain footprints are shown as either:
(i) Specific hits–indicating high confidence in the anno-
tation with an NCBI-curated model, where the
query model alignment score exceeds a model-
specific threshold (10).
(ii) Superfamily annotation, where each superfamily is a
protein fragments, often quite redundant.
(iii) Annotation by multi-domain models, which have
been excluded from the superfamily clustering as
they tend to group non-homologous fragments
into the same cluster.
By default, CD-Search displays only the highest ranking
domain superfamily annotation for a given region on the
query (and there can be no more than one specific hit, if
any). The default display also shows only the highest
ranked multi-domain model for a given query region,
and only if that alignment is nearly complete with
respect to the model. An alternative view shows the full
alignment results, listing the individual models from all
source databases that could be aligned to the query with
significant scores. Often, the full alignment results are
FUNCTIONAL SITE ANNOTATION
Conserved Domain Models curated by NCBI often come
together with the location and characterization of func-
tional sites, such as active sites or binding sites for cofac-
tors, nucleic acids, ions and polypeptides. These are
recorded together with evidence, such as explicit complexes
observed in experimentally determined 3D structure or the
published literature. Sites are recorded only if it seems clear
that they can be mapped onto a majority—if not all—
members of the protein family modeled by the domain
alignment. The query-to-model alignments computed by
RPS-BLAST can be used to transfer site annotation onto
the protein query. Currently, 13562 sites have been
recorded on 5214 models (?86% of all NCBI-curated
conserved domain alignments). Site annotation derived
from CDD is visible in the default display of sequence
records in the Entrez/Protein database, and functional
site descriptions together with evidence can be examined
in detail on the conserved domain summary pages, which
are accessible via Entrez/CDD. The CDTree/Cn3D
software, which is available for MS Windows and Mac
OS X platforms, can be utilized to visualize conserved
domain hierarchies, alignments, annotations, functional
sites and corresponding evidence in great detail. CDTree
and Cn3D are helper applications that can be launched via
the conserved domain summary pages, and they are also
the main curation tools used in the CDD project.
PROTEIN SEQUENCE ANNOTATION ON A
As pre-computed domain annotation is available for se-
quences in the Entrez/Protein database (excluding se-
quences associated with metagenomes), and as live
searches for sequences not represented in Entrez can be
run quickly, CDD may be used to compute and/or retrieve
protein sequence annotation for large sets of query se-
quences. We have implemented a novel interface, Batch
CD-Search, which facilitates the processing of upto
100000 protein queries at a time. Queries can be
supplied as either protein GIs (unique numerical identi-
fiers used in Entrez/Protein), protein accessions or raw
sequence data. Batch CD-Search then compiles the
complete results, loading the domain hits on each query
sequence into a temporary data base, which lets the user
extract various results subsets, such as domain hits, align-
ment details and functional sites for up to several days
after the search. The data can be downloaded in various
formats including tab-delimited text (Figure 2), or dis-
played graphically within a web browser to show
detailed annotations on any individual protein from the
query list, using the ‘browse results’ function.
D226Nucleic AcidsResearch, 2011, Vol.39, Database issue
While large sets of queries can be uploaded conveniently
via the web interface, Batch CD-Search can also be
accessed programmatically via its URL; corresponding in-
structions are given in the help documentation.
Table 1 lists the Batch CD-Search URL, among other
CDD-related resources. An alternative to using the Batch
CD-Search service for the annotation of local data sets
would be to run RPS-BLAST locally. CDD distributes
pre-built search databases via the CDD FTP site, and
also distributes individual position-specific score matrices
combinedwith locally generated
special-purpose RPS-BLAST search databases.
The authors thank the authors of Pfam, SMART, COG,
TIGRFAM and NCBI’s Protein Clusters database, and
Figure 1. Conserved domain annotation on a well-characterized protein sequence. Shown here is the default concise view generated by the
CD-Search tool, using pre-calculated alignment information. The view is divided into two panels: a graphical summary and a table detailing the
individual matches. The query sequence coordinates are indicated on a gray bar in the top portion of the graphical summary. ‘Specific hits’ to
NCBI-curated domain models are positioned in a separate area below the query sequence, with corresponding balloons rendered in saturated colors.
The extent of the best-scoring hit for a region on the query also determines the annotation with the corresponding conserved domain ‘Superfamily’.
‘Superfamilies’ are positioned in the area below the ‘Specific hits’, and together these are enclosed in boxes to indicate superfamily membership of
the NCBI-curated models. If the full (detailed) results display is selected, an area summarizing ‘Non-specific hits’ will be shown as well, and the
corresponding boxes will be drawn so as to resolve their superfamily relationships; the highest ranked match for each superfamily defines the extents
of the corresponding box. ‘Non-specific hits’ and ‘Superfamily’ balloons are rendered in pastel colors, with each superfamily being assigned a
separate color. Matches to ‘multi-domain’ models are rendered as gray balloons in a separate area of the summary graph. Only the best-ranked
non-overlapping multi-domain models are shown. Functional sites, as annotated on NCBI-curated domain models, are mapped to the query
sequence and depicted as triangles. Sites are mapped from the highest ranked model only, and they are colored according to their source. Both
conserved domain balloons and site annotations are hot-linked, so that moving the mouse over the objects displays additional information, and so
that clicking on the objects launches conserved domain summary pages for the particular domain model, embedding the user query sequence in the
alignment for further analysis, if applicable. A tabular view below the graphical summary lists E-values, multi-domain status and various identifiers
for the conserved domain models identified as matches. The table rows can be expanded to display a detailed pair-wise sequence alignment between
the query sequence and the domain model’s consensus sequence. An alignment of all sequences comprising a domain model, with or without the
query sequence embedded, is accessible by clicking on the domain’s balloon representation in the graphical summary or its unique accession in the
tabular summary, respectively.
Nucleic Acids Research, 2011,Vol.39, Database issueD227
Paul Thiessen and the NCBI Information Engineering
Branch for assistance with software development. They
also thank the referees of the manuscript for helpful
Funding for open access charge: Intramural Research
Program of the National Library of Medicine at the
National Institutes of Health/DHHS.
Figure 2. The web-interface to Batch CD-Search. An input dialogue lets the user specify a set of protein queries or upload a corresponding file. The
preliminary results page (not shown here) provides controls for downloading results in a variety of formats. The sample download format featured
here lists one annotation per line, specifying the protein query, the type of domain hit (specific hit, superfamily or multidomain), from–to intervals on
the query, E-value and score and the domain model’s name and accession. The Batch CD-Search help document describes the additional download
options and formats available.
Table 1. URLs and other resources associated with the CDD project
Database home page
CDD help documentation
CD models and alignments, pre-built search databases
Live and pre-computed RPS-BLAST
Live and pre-computed RPS-BLAST
Domain hierarchy viewer and editor
Stand-alone tool for searching databases of profile
models, part of the NCBI toolkit distribution
executables can be obtained from:
D228 Nucleic AcidsResearch, 2011, Vol.39, Database issue
Conflict of interest statement. None declared. Download full-text
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