Comparison of the ATP Sites/Structural Similarity Between Murs

[mattodd]

Hi @eyermanncj - I was wondering if you could post the analysis you did of the comparison between the ATP binding sites of the various murs. @ZigBu has been looking at this a little, and I wanted to ensure that there was no duplication and that she could learn from your work.

I think this was the slide you generated, but let me know if not, and let me know if there's more here that might help Zige do the comparison. @chrisdowson1 may also have a view/data here.

Zige was also saying that there appears to be greater similarity in structure between MurC&D and between MurE&F than between other pairs. Is that right? (if yes then that provides some strategy about which murs we ought to be trying to inhibit with single molecules.

[eyermanncj]

That is the analysis I have done. I never looked at murF. Focus has been on the murC and murD pair.

[Yuhang-CADD]

Replying to: Zige was also saying that there appears to be greater similarity in structure between MurC&D and between MurE&F than between other pairs. Is that right? (if yes then that provides some strategy about which murs we ought to be trying to inhibit with single molecules.

@ZigBu could you please provide your reference for this colculsion please? Many thanks!

[ZigBu]

@mattodd @Yuhang-CADD For the point that there is similarity between the MurD/MurC and MurE/MurF, there is a miss understanding here, I apologise for not explaining myself clearly. According to the previous articles, all the Mur ligases share similar topologies of the C-terminal and the central domain. While the N-terminal domain of MurC/MurD and MurE /MurF shows differences due to the various length of the UDP-precursor substrates. (DOI)

Another research provides a more clear analysis upon this point. It is stated that MurC and MurD share a common Rossmann-type α/β fold and have a very similar structure and topology for N-terminal domain . MurE and MurF on the other hand have α/β fold with different topology and a mixed β- sheet compared with the all-parallel β-sheet in MurC/MurD. (As shown in the Figure7 of the article) In addition, the two groups of enzymes bind to the UDP part of the substrate in significantly different ways. This difference in folding and binding may be related to a series of reactions on extended substrates catalyzed by Mur ligase. (DOI)

So my estimation is that if the compound is targeting the UDP binding site. Then considering the similarity between enzyme structure. MurC/MurD would be a more promising pair with MurE and MurF on the other side. However MurD/MurE dual inhibitors, which targeting close to the UDP binding site, have been reported with activities against Escherichia coli and Staphylococcus aureus with IC50 values between 6.4 and 180 μM(I am not quite sure about whether it is promising or not). (DOI) Other than that, the mouthly meeting at 11.9 stated the compound that is effective againt MurC has less response to the MurD. I have some questions on this point. Is this compound targeting the UDP or other allosteric binding site?

If you could help to explain or point out my misinterpretation! Thank you so much!