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closeIssues should be addressed
Posted by yusuf on 20 Jun 2013 at 16:01 GMT
In this paper authors have modeled Wnt1 and FZD1 CRD proteins and they docked these two proteins to form a complex. Computational validation and biological consequences of this modeled structure have been discussed in the article at length.
There are some important issues, which should be addressed
1. The claims made by authors based on only the computational predicted model is a bit exaggerated.
2. Authors seem to have contradicted themselves by first denying and then again mentioning the xenopus Wnt8-Mouse frizzled receptor8 cysteine rich domain (CRD) complex structure [Janda et al, Science 337: 59-64(2012)]. In this break-through research article, Janda et al, clearly mentioned the novel fold consisted of a "hand" with a "thumb" and "index finger" which clearly overlaps with the authors claims about the U-shaped binding pocket of Wnt proteins. In conclusion, authors have not reported anything new although the quality of work done to reach the present level is quite impressive, but the analysis seems to be highly misplaced or contradictory.
3. Conserved residues highlighted in the structural analysis may be mutated and studied in the laboratory for the failure of binding of CRD with the Wnt protein.
4. Authors may also try to look into the binding specificities between Wnt and FZD proteins across the species to arrive at some logical conclusion.
RE: Issues should be addressed
MAKamal replied to yusuf on 29 Jun 2013 at 01:39 GMT
1. The main aim of this study was three folds. Firstly, to model the human protein structures (ligand and receptor) from the templates and secondly, to determine the mode of interaction between the two proteins. The third and main purpose was to locate the critical residues (either of receptor or ligand) involved in binding interactions, so that these residues could be targeted for designing drugs. Our computational study overlaps with Janda et al., 2012 as the mode of binding is found to be similar, however, Janda described it as a hand palm grasping the WNT ligand with a thumb and index fingers, whereas, we named it a U-shaped cup/groove holding the interacted ligand. The study is novel with respect to origin of protein because it deals with the human proteins, unlike Janda (mouse proteins). Also because of the main objective of the study, which is to locate and highlight the critical binding residues. The inhibitors designing against these residues using structure based, ligand based and pharmacophore based approaches is one of the future aspect of this study.
2. The first step of finding the critical residues was to check the gene expression of related gene/protein in normal and tumor tissues, which was successfully done and explained in our another study (Ain et al., 2011). Following that study, we extracted the WNT genes responsible for tumourgenesis and projected for structural details of proteins and their interactions with receptors, causing the irregular activation of WNT signalling pathway. Along with these structural details we focused on locating the conserved residues and proposing for targeted drug therapy. The mutagenesis and related experimental studies details might not fall in the scope of this article, but can be employed in future work.
3. The present study was only focused on predicting structure of human Wnt and CRD complexes and after successfully completing 1st part then interaction of CRD units was subject to study. To study Wnt interaction across species was out of scope in present context. Therefore in future we would certainly involve these aspects across all Wnt(s) and species.