D362–D369 Nucleic Acids Research, 2012, Vol. 40, Database issue doi:10.1093/nar/gkr914 Published online 12 November 2011 MIPModDB: a central resource for the superfamily of major intrinsic proteins Anjali Bansal Gupta1, Ravi Kumar Verma 1 , Vatsal Agarwal2, Manu Vajpai1, Vivek Bansal1 and Ramasubbu Sankararamakrishnan1,* 1Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016 and 2Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India Received August 12, 2011; Revised October 5, 2011; Accepted October 8, 2011 ABSTRACT The channel proteins belonging to the major intrin- sic proteins (MIP) superfamily are diverse and are found in all forms of life. Water-transporting aquaporin and glycerol-specific aquaglyceroporin are the prototype members of the MIP superfamily. MIPs have also been shown to transport other neu- tral molecules and gases across the membrane. They have internal homology and possess con- served sequence motifs. By analyzing a large num- ber of publicly available genome sequences, we have identified more than 1000 MIPs from di- verse organisms. We have developed a database MIPModDB which will be a unified resource for all MIPs. For each MIP entry, this database contains information about the source, gene structure, se- quence features, substitutions in the conserved NPA motifs, structural model, the residues forming the selectivity filter and channel radius profile. For selected set of MIPs, it is possible to derive structure-based sequence alignment and evolution- ary relationship. Sequences and structures of se- lected MIPs can be downloaded from MIPModDB database which is freely available at http://bioinfo .iitk.ac.in/MIPModDB. INTRODUCTION Major intrinsic proteins (MIPs) form one of the largest superfamily of channel proteins (1,2). They transport water, neutral solutes such as glycerol and urea, metalloids including antimonite and arsenite and gases like CO2, nitric oxide and ammonia across the membranes (3–5). Water-transporting aquaporin and glycerol-speciﬁc aqua- glyceroporin are the prominent members of this family. Members of MIP superfamily are involved in vital physio- logical processes such as skin moisture, gastrointestinal ﬂuid transport, fat metabolism, epidermal proliferation, maintaining corneal and lens transparency in eyes and water homeostasis in kidney and central nervous system (6–11). MIPs are found from bacteria to humans and a large number of diverse MIP members have been identi- ﬁed especially in plants (12–17). The abundant MIPs identiﬁed in higher plants can be classiﬁed into at least ﬁve major subfamilies (15). In humans, they are implicated in several diseases such as nephrogenic diabetes insipi- dous, acute and chronic renal failure, brain edema, cata- ract and arsenic toxicity (18–24). Sequence analysis of MIP members clearly revealed the presence of highly conserved Asn-Pro-Ala (NPA) signature sequence motif (25,26). MIP sequences also possess internal homology in which the N- and C-terminal halves have signiﬁcant sequence similarity (25). At the structural level, the N-terminal half is related to the C-terminal half by a pseudo-2-fold symmetry (27,28). Three-dimensional struc- tures of more than 10 MIPs from different organisms such as mammalian (29–31), plant (32), Escherichia coli (33), yeast (34) and archaea (35) have been determined. They all adopt a unique hourglass fold even when the sequence identity among them is very low. Two regions of constric- tion have been identiﬁed within the channel. The two NPA motifs form the central constriction and the outer con- striction is toward the extracellular side known as aromatic/arginine (ar/R) selectivity ﬁlter formed by four residues. Both regions are known to play important role in the solute transport and selectivity (36–39). With their in- volvement in human physiology and pathophysiology and with the available structural knowledge, members of MIP family are being considered as attractive drug targets (40,41). For example, aquaglyceroporin in intracellular parasite Plasmodium falciparum and its structural know- ledge (42) has opened new options for novel malaria therapies (43). However, for the majority of MIPs from large number of organisms, the tissue localization, their functional properties and the biological signiﬁcance are either not known or they are not clearly understood. *To whom correspondence should be addressed. Tel: +91 512 259 4014; Fax: +91 512 259 4009; Email: rsankar@iitk.ac.in The Author(s) 2011. 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/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.