How are you?

Yesterday I emailed you about shi’s new science paper. Last night I really scrutinized these two structures based on their density map.

Now I have slightly different conclusions now, which I listed below for clarification. I am also sorry for any misleading.

1) The mutation studies from both papers are correct, which can be obtained without the structures. The key residues are W93(the common residue in both papers), W202, W293, plus two more residues identified in Shi’s paper, E208 and Y365. Actually, all these five residues are close to each other in the 3-D structures, indicating that they all are involved in the substrate binding or the opening of the binding pocket, which is also waiting for the substrate complex structure to further prove.

2) When it comes to the structures, Chis Miller’s structure is totally correct, resulting in the correct positioning of all the residues. Basically, SHi’s structure is 40% wrong. Why I say this? The reason is that Shi’ group correctly positioned the residues from 1 to about 160, but they were wrong after the point in terms of side chain asignment because the poor density map of shi’s structure did not allow this fine assignment. Even worse, when shi’s group built the structure model, they shifted the entire structure about 10 angstom like you translate your tea cup a little bit on you desk. That is why Chis Miller mentioned that there is a 3-4 residue shift in shi’s structure.

Although shi did not purposely to make such mistake, this is a huge mistake in this field.

To to a very strict crystallographer, the proper way is just to assign the main chain atoms if you can not see the side chain atoms in the density map and check all the validation parameters to make sure the main chain position is right. Apparently, SHi’s graduate student or he himself did not pay enough attention to model building.

3) No more words can be added to the scientific stringence. Shi should admit this misrake and respond to this. We will see!

Have a nice summer,

Jerry Ni

How do you do!
I am very sorry for not being able to input Chinese in my computer. But I think I have something to say. Therefore, I am trying hard here to make myself clear. If I am wrong, please feel free to correct me.

Personally I have not met you before.However, I always look forward to reading your scientific essays on the “XYS” website. A lot of people like me admire your courage to fight against the scientific misconduct in China and appreciate your efforts to provide the wonderful platform for communication. Very best luck with your work.

My topic is about Shi yigong’s new Science paper on AdiC transporter. Firstly I am not one of his fan. On the contrast, I have different opinions about what he has done so far in China, including not only his social events but also his scienfic visions, as many people who are discussing on “XYS”.

Why I pay attention to his new paper is that you posted an essay yesterday saying that his paper could be wrong and was appealing for further investigation. I am not fully sure about what kind of investigation you want to propose. According to your essay followed by Yan yang’s even emotional comments, that could be some “misconduct-like” investigation, which I do not think is necessary.

Once again, I want to make myself clear that I am not his fan. The purpose of this email is purely for scientific discussion. I think his paper is a very good paper since I was trained as a crystallographer and am still in this field. I list the main conclusions in the following:

1) The superposition of Shi Yigong ’s AdiC structure with Chris Miller’s structure indicates that they are almost the same(more than 90%), except for some flexible loop regions outside the main helix bundle core. It is uderstandable that you may get slightly different conformations when it comes to membrane proteins, especially when you are using differenct ditergents and crystallizing them in different conditions using different methods.

2) In the opinion of crystallographers, 3.2 angstrom resolution is more or less that same as 3.6 angstrom resultion. They are the same low resolution structures and have very similar refinement parameters, indicating they are both right and have the same quality.

3) In terms of the functional studies to support the structures, They are both excellent even Shi yigong did slightly better. Since the structure is remarkably similar to that seen in several Na+ transporters and the complex structure of Na+ transporter is available, the structure alignment itsself suggests a conserved binding pocket, including key residue Y93. One could reasonably imagine that Adic, the Arginine transporter, should have a bigger binding pocket involving a couple of residues because it transports bigger substrate like L-argnine rather than Na+ ions. The mutation studies from both papers verified the role of Y93. Chris Miller’s paper suggests two more residues, W202 and W293. SHi Yigong’s paper used more mutants and identified E208 and Y365. First thing is that the transporting assays in two papers are very solid using different mutants. Why did Dr.Fang conclude that Shi’s Science paper is wrong? I guess you think these residues are not consistent with each other. Two things can explains this discrepancy. One is: Chris miller ’s AdiC structure is from Salmonella, and Shi’s AdiC is from E.coli. Although the amino acid sequence is 95% identical. They still have many different residues. Let us say, the W293 in Chris Miller’s structure is corresponding to Serine289 in Shi’s structure. It is reasonable that these two transporters could share some residues but also use different residues. Another thing is very like the story about the indian blind and the elephant. Let us assume that 10 residues would be involved in the transportation. It is not surpurising that Chris Miller indentified these three and Shi’d identified the other several. By the way, I want to make a comment here that Shi yigong proposed a role for E208 in the binding of L-arginine, which is new and very juicy.

4) The last thing is that both papers need a complex structure to nail down the exact mechanism. As for a Chinese, I do hope that Shi will get it at first. IT could have very important pharmaceutical meanings, for example, structure-base drug design could provide a specific inhibitor to block these two virtual proton pumps, thus kill the enteric bacteria.

Thanks a lot for your patient and time to read this. Many more thanks if you are willing to post it one “XYS”.

All the best to you,

Yours sincerely,

China-101