Questions and AnswersProf. Dirk Heinz

Proteins are strings of amino acids. Genome researchers have already told us what the sequence in these strings is. So what new insights can your area of expertise - structural biology - even bring us?

Proteins are made of amino acid chains that - independently from their sequence - coil and bend in a specific way. This three-dimensional structure is the deciding factor for the correct functioning of the organism. We now show what this structure looks like exactly. Which means that, in the end, we have a model for a protein that shows every single atom in its exact alignment in space, as it is found in nature. We can, for example, also say exactly where on a host cell an agent will settle, or what a slot - in which an antibiotic might fit - looks like.

If you consider the lock-and-key principle in biology textbooks, you may find an antibody presented as a triangle and fitted perfectly to the surface of a virus. Is it possible for you to tell us, what such a key looks like exactly?

Yes, that comparison works pretty well - we already knew that it had to work like a key that fits in a lock. Now, we can say exactly how every tooth of the key is formed and what the lock that fits this key looks like. Those are very important insights. Because with them we can, for example, on a computer specifically design molecules that fit this lock in order to make antibiotics. We don’t need to resort to ‘trial-and-error’.

The central Protein Data Bank, in which all structural biologists store their data, grows and grows - about 70.000 compounds can be found there by now - what did infection researchers contribute to this?

That is difficult to quantify. On one hand, we do not know how many different compounds we actually have in the Data Bank. Some of the data may exist in duplicates or may be so similar that we can’t be sure if we’re really dealing with different molecules. And one other thing: We still know very little. This can be shown with the example of a simple Escherichia coli bacterium. This bacterium has about 4.300 genes, codes for proteins. In humans, it’s about 20.000 genes. Therefore, we have only thrown light on the structure of a tiny fraction of all proteins. And we do not know yet how many of these, play a part in infection processes - there is a lot left to do, a lot.

Even is the comparison is a little off: Meanwhile, genome researchers can sequence a complete human genome in less than a couple of hours. Why does it take structural biologists so long to do their analyses?

In genome analysis, research is profoundly automated by now. It’s not the same for us. We are currently still developing procedures. And we also have several “bottle-necks” that still render it impossible to “simply” analyze compounds. It starts with the fact that we need quite large amounts of a protein we wish to analyze. Therefore, we must first find a way to even produce our proteins in these quantities. Sometimes this is not very easy, especially for large, complex compounds. We then have to grow crystals out of these solutions, because we can only analyze them in the crystalline form. Finally we have to get access to the machines that we need in order to do the analyses, as for example the synchrotron radiation source. There aren’t many of these and experimental facilities are much sought-after. Consequently, we face several tasks at once: We must continue developing procedures and at the same time analyze structures.

What was the greatest success up to now that the infection researchers among structural biologists have been able to show up for?

As mentioned before: A lot that structural biologists have discovered isn’t easy to assign to a certain area of expertise. The human organism and also the disease agents, that attack us, are too complex for that. If you ask me about the most important finding in structural biology, then I’d have to say the unraveling of the ribosome structure - which was then also worth a Nobel Prize. If you ask me which the most important finding in infection research is, then I’d also say: The unraveling of the ribosome structure. Because this structure gives us many points on which future, novel antibiotics can dock on to. And these are no dreams of a basic researcher. Nowadays, there are several companies that have rushed to developing antibiotics using exactly these points of approach.

You yourself are a chemist: How easy is it to find your place in the biosciences?

I feel perfectly at home where I am right now. Even if the name suggests differently, structural biology is not a bioscience. At the beginning, almost only physicists worked in this field. Our analyses methods originate from physics. Little by little the chemists came in, like me. We bring knowledge on the chemical properties of compounds and we know for instance how one must prepare proteins in order to analyze them. Only recently, more biologists also work in structural biology. The biologists can produce the proteins that we wish to examine. And they have knowledge on the general mechanisms that underlay infection processes. This interface between biosciences and a very technical field of study - that is the perfect place for me.

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