Nucleic Acids Research Advance Access originally published online on October 2, 2008
Nucleic Acids Research 2009 37(Database issue):D338-D341; doi:10.1093/nar/gkn599
Nucleic Acids Research, 2009, Vol. 37, Database issue D338-D341
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
JAIL: a structure-based interface library for macromolecules
Stefan Günther1,
Joachim von Eichborn1,
Patrick May2 and
Robert Preissner1,*
1Institute of Molecular Biology and Bioinformatics, Charité-University Medicine Berlin, Arnimallee 22, 14195 Berlin and 2Max-Planck-Institute for Molecular Plant Physiology, 14476 Potsdam-Golm, Germany
*To whom correspondence should be addressed. Tel: +49-30-8445-1649; Fax: +49-30-8445-1551; Email: robert.preissner{at}charite.de
Received August 20, 2008. Accepted September 4, 2008.
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ABSTRACT
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The increasing number of solved macromolecules provides a solid
number of 3D interfaces, if all types of molecular contacts
are being considered. JAIL annotates three different kinds of
macromolecular interfaces, those between interacting protein
domains, interfaces of different protein chains and interfaces
between proteins and nucleic acids. This results in a total
number of about 184 000 database entries. All the interfaces
can easily be identified by a detailed search form or by a hierarchical
tree that describes the protein domain architectures classified
by the SCOP database. Visual inspection of the interfaces is
possible via an interactive protein viewer. Furthermore, large
scale analyses are supported by an implemented sequential and
by a structural clustering. Similar interfaces as well as non-redundant
interfaces can be easily picked out. Additionally, the sequential
conservation of binding sites was also included in the database
and is retrievable via Jmol. A comprehensive download section
allows the composition of representative data sets with user
defined parameters. The huge data set in combination with various
search options allow a comprehensive view on all interfaces
between macromolecules included in the Protein Data Bank (PDB).
The download of the data sets supports numerous further investigations
in macromolecular recognition. JAIL is publicly available at
http://bioinformatics.charite.de/jail.
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INTRODUCTION
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Proteins interact quickly and specifically with each other or
with nucleic acids. All interactions form a biochemical network
that reflects the high complexity of cellular metabolism. Nevertheless,
the vast majority of all interactions are not yet identified
and are subject to current research (
1). An important step towards
the mechanistic descriptions of such interactions is the 3D
structural information of macromolecules. However, complexed
proteins are difficult to co-crystallize and the number of publicly
available X-ray structures in the Protein Data Bank
(PDB) (
2)
is very limited (
3). Thus, a structure-based analysis of particular
interacting macromolecules is often only possible by using docking
models. For systematic analyses the problem of the low number
of protein–protein complexes might be avoided by taking
into consideration interacting domains or chains. Such types
of interfaces often exhibit a similar behaviour like those of
interacting proteins (
4). For instance, knowledge-based potential
functions that represent the co-occurrence of certain residues
might be similar for contacts between domains of a single chain
as well as contacts between proteins. Another approach is the
utilization of the interfaces between domains or chains to detect
structural similarities to binding sites of interacting proteins.
First applications apply this method for protein–protein
complex modelling (
5). Consequentially, some structure-based
databases exist that focus on the interacting parts of proteins.
SCOPPI (
6), SNAPPI (
7) and PIBASE (
8) classify interfaces between
domains, the domain information was retrieved from SCOP (
9),
CATH (
10) or Pfam (
11). Since they depend on domain definitions
extracted from secondary databases especially structures solved
during the last few years are normally not yet classified (
12).
HotSprint (
13) focuses on conserved residues in chain contact
sites and is regularly updated but domain information is ignored.
Dockground (
3) comprises the so far most comprehensive data
set of interacting proteins and chains respectively. The excellent
database also provides user defined data sets of the associated
unbound protein-binding sites. Nevertheless, it focuses on protein–protein
interaction, so information about intra-chain contacts is not
retrievable. None of the mentioned databases contains interfaces
between proteins and nucleic acids. Although each application
is useful to enlighten questions the database is specialized
for, a comprehensive web resource that combines all the different
kinds of interfaces between macromolecules is not available.
Furthermore, the database should be characterized by regular
updates and the opportunity to download appropriate data sets.
To overcome this lack we developed JAIL, a structure-based interface
library for macromolecules.
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DATABASE
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Currently, the database contains more than 184 000 interfaces
that are composed of four different fractions: 81 000 interfaces
between domains classified by SCOP, 76 000 interfaces between
different protein chains, 8000 interfaces between proteins and
nucleic acids and 19 000 interfaces which were calculated based
on the assumed biological units. Since they were not directly
solved cristallographically, they are annotated separately.
The interfaces result from the evaluation of 52 000 different
asymmetric unit files as well as the associated biological unit
files provided by the PDB. An interface is defined as those
atoms of a chain or domain that are located within a range of
10 Å around the C
-atoms of the interacting counterpart.
In the case of nucleic acids the backbone (P/C4')-atoms were
considered. Each binding site has to consist of at least five
C
-atoms as the case may be backbone atoms of the nucleic acids.
Assumed biological units were calculated based on the first
two models build up by reflection of the unit cells. Information
on the evolutionary conservation was extracted from the HSSP
database (
14). The PDB-IDs of nucleic acids containing structures
were retrieved from the Nucleic Acid Database (
15). All chains
of the database were sequentially clustered using the regular
updated lists provided by the PDB calculated by the Cd-hit program
(
16). Thus, it is possible, to select interfaces of proteins,
which are similar in sequence to each other as well as to download
non-redundant data sets based on protein sequences. Structural
clustering was implemented by the selection of representative
interfaces of each family–family or superfamily–superfamily
contact between domains classified in SCOP. A protein can be
identified by a detailed search form that allows searches by
PDB-ID, protein name, EC-number, UniProt accession number or
SCOP-ID. An implemented full text search allows the screening
to the full header information of the structure-file as well
as the SCOP domain descriptions. Visualization of the interfaces
was implemented by pre-generated thumbnails of each interface
and on the other hand by the interactive protein visualizer
Jmol (
http://www.jmol.org). The download section provides various
possibilities to build up a user defined data set. Structurally,
clustered interfaces based on the SCOP domain definitions as
well as sequentially clustered interfaces based on protein chain
clustering are separately retrievable but can also be combined.
Parameters like the SCOP-hierarchy (family/superfamily) or the
sequence identity level (50%, 70%, 90% and 95%) are selectable.
The database is automatically updated six times a year.
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EXAMPLE OF USE
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The provided browsable interfaces support the answering of various
further investigations. One of them is the comparative study
of molecular recognition of nucleic acids and proteins. For
instance, experimental evidence exists, that proteins mimic
nucleic acids to usurp the role of interacting macromolecules
(
17,
18). Shape comparisons of different kinds of interfaces
(protein–protein/protein–nucleic acids) may help
to identify cases of molecular mimicry.
A matter of particular interest in this context is the identification of protein domains that interact with other proteins as well as with nucleic acids. Figure 1 shows an example of a search for such a case by using the implemented ‘Show related proteins’-option. Figure 2 shows the resulting interfaces of a fab-fragment in complex with an enzyme. The same domain architecture is also capable to bind single stranded hairpin DNA.
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Figure 1. Example for a search by homology. (a) Entry of PDB-ID 2FR4. The highlighted link (Show related proteins) yields a list of homologous proteins. (b) List of homologs of 2FR4 and the associated interfaces. The last entry is PDB-ID 2J88 and is shown in Figure 2b.
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Figure 2. Two similar Fab-fragments (sequence identity >95%) which interact with different kinds of macromolecules. The complexes were identified with the homology search option (see Figure 1) of JAIL. (a) Fab-fragment in complex with a stem-loop DNA (PDB-ID: 2FR4). (b) A monoclonal IgG Fab-fragment in complex with hyaloronidase (PDB-ID: 2J88).
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FUNDING
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Deutsche Forschungsgemeinschaft (DFG SFB-449); the International
Research Training Group on Genomics and Systems Biology of Molecular
Networks (GRK1360); German Federal Ministry of Education and
Research (GoFORSYS Grant Nr. 0313924 to PM). This work is licensed
under a Creative Commons Attribution-Noncommercial-Share Alike
3.0 License. Funding for open access charge: Deutsche Forschungsgemeinschaft
(SFB-449).
Conflict of interest statement. None declared.
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ACKNOWLEDGEMENTS
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The authors want to thank Björn Grüning for maintaining
the webserver.
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ABSTRACT
INTRODUCTION