lars20070/gist:2af9503158adb7cedb93189f52e0e1d6

## gistfile1.txt
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JOHANNA:

In this work, the group of cis-3-selective PiHs (cis-Pi3Hs) from bacteria is described based on the PiH GetF identified by Müller et al. With the archetypes GetF and PiFa, the cis-Pi3Hs form a monophyletic clade that is catalytically distinct from cis-proline-3-hydroxylases (cis-P3Hs). In vitro conversions showed that GetF and PiFa have a limited substrate tolerance that is dissimilar to the relatively promiscuous cis-P3H: whereas Pip and methylprolines were readily hydroxylated, Pro and smaller derivatives were virtually excluded as substrates. The ability to discriminate between chemically very similar substrates is most likely based on accurate structural differences in the active site. Structural modeling of GetF and molecular docking revealed side chains that are supposed to be responsible for the specificity. Site-directed mutagenesis was used to modify GetF towards a Pro-tolerant activity; however, the variations did not result in a change of substrate specificity. The results suggest that mutual effects of substrate position, substrate conformation, and structure of the active site relate to the pronounced specificity in PiHs.

GPT-2:

Further mechanistic studies are needed to determine how this system of the mitochondrial P3Hs is involved in maintenance of its substrate specificity. An alternative strategy for this problem may involve modifying the outermost surface polymers that are important in initiating protein–protein interactions and structural protein–substrate interactions that are important in guiding protein–substrate interactions [28]. The most studied coating proteins include P10, P11, P2, and P3. P10 and P11 have hemisubstituted rim rings whereas P2 is highly conserved and does not occur in other species. In fact, the general structure of P2 in both stable and non-stable state (SS) forms are similar to that of the beta-amyloid protein of AD [6] [29]. Our results show that several proteins of this family exhibit mitogen-activated protein kinase (MAPK)-dependent conformational flexibility: for example, for P3 the interaction between the beta-sheet and the n-terminal metalloprotein was of intermediate length (average k A = 16.3–16.9 kDa), and the zinc finger-like domains are seen throughout the transition region, indicating that the extracellular domain is only partially closed (Table S2). Because these proteins are held in the aggregates in a periodicity of ~7 s, an additional key step is required to initiate protein–protein interactions: the protein-binding domain of pore water must bind to a protein in its intermolecular conformational landscape. This is done by the first important α-helix β-sheet interaction in the alpha helix, to which MAPK receptors are involved [30] and in which the peak k A is ~15 kDa.

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THERESA:

Coronaviruses. For my part, I actually didn't know anything about them, until the beginning of this very special year 2020. And then this year everything turned upside down and by now you have probably all heard enough of the latest coronavirus strain, SARS-CoV2. For those of you who spent the last months on Mars: SARS-CoV2 is the third strain of coronaviruses that recently expanded its range of host animals successfully to include humans and in this new host, us, can trigger serious respiratory diseases. The first two coronaviruses to “achieve” this were SARS-CoV, which triggered the first pandemic of the 21st century in 2002/03, and MERS-CoV, which is around since 2012. Of these three viruses, MERS-CoV appears to be the deadliest. However, since it rarely transmits from person to person, it spreads very slowly (although there is a very real danger that this could change at some point). The first (2003) SARS-CoV in many aspects is very similar to the current SARS-CoV2. They are surrounded by a fatty shell, which is why they can be easily destroyed by soap or disinfectant. The so-called spike proteins (shown in the image in red) sit in this fatty sheath and can bind to certain proteins on cell surfaces in order to allow the virus to penetrate the host cell membranes. Both SARS coronaviruses bind with their spike protein to the same surface proteins on our cells: ACE2 and TMPRSS2, whereby – after a few rounds of mutations - the new SARS-CoV2 binds to ACE2 with 10-20-fold higher affinity than the original SARS-Virus did. This contributes significantly to the new SARS-CoV2 being so particularly infectious. Both ACE2 and TMPRSS2 thus are currently being researched intensively. This is done primarily with regard to possible therapies that could target these proteins. In this article I will introduce you to the ACE2 protein, next week I will present you TMPRSS2.

GPT-2:

The ACE2 protein is the first protein encountered by the virus during cell-to-cell contact. It is however less likely to be targetted by immune cells in our body than most other proteins, for it is no longer protected from immune destruction by the body's immune system as it was in the original SARS-CoV1. Therefore its presence would be somewhat welcome - as might be the potential for a new anti-viral drug that is able to selectively target the infected cell. So let's first have a look at the protein of interest. As you can see, ACE2 consists of 26 amino acid residues arranged in two "chains" each of which comprises 12 amino acids. Thus the total ACE2 protein chain comprises 71 amino acids and requires the usage of one molecule (since any longer protein chain would be too long to fit into the cell's outer membrane, and because small chains of amino acids don't have an extremely high uptake by the cell membrane, although they would be very high-affinity for the virus's plasma membrane). This leads us to the next question - how is the ACE2 protein adapted to its new role? It is unlikely that there are many amino acids in the cell membrane, so if there are any left, they would probably have to be left over in one of the 3 folding steps in which the ACE2 proteins are folded into a given α/β complex. We'll take a look at each of these steps in turn and see what possible amino acids there are left.

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	JOHANNA:

	In this work, the group of cis-3-selective PiHs (cis-Pi3Hs) from bacteria is described based on the PiH GetF identified by Müller et al. With the archetypes GetF and PiFa, the cis-Pi3Hs form a monophyletic clade that is catalytically distinct from cis-proline-3-hydroxylases (cis-P3Hs). In vitro conversions showed that GetF and PiFa have a limited substrate tolerance that is dissimilar to the relatively promiscuous cis-P3H: whereas Pip and methylprolines were readily hydroxylated, Pro and smaller derivatives were virtually excluded as substrates. The ability to discriminate between chemically very similar substrates is most likely based on accurate structural differences in the active site. Structural modeling of GetF and molecular docking revealed side chains that are supposed to be responsible for the specificity. Site-directed mutagenesis was used to modify GetF towards a Pro-tolerant activity; however, the variations did not result in a change of substrate specificity. The results suggest that mutual effects of substrate position, substrate conformation, and structure of the active site relate to the pronounced specificity in PiHs.

	GPT-2:

	Further mechanistic studies are needed to determine how this system of the mitochondrial P3Hs is involved in maintenance of its substrate specificity. An alternative strategy for this problem may involve modifying the outermost surface polymers that are important in initiating protein–protein interactions and structural protein–substrate interactions that are important in guiding protein–substrate interactions [28]. The most studied coating proteins include P10, P11, P2, and P3. P10 and P11 have hemisubstituted rim rings whereas P2 is highly conserved and does not occur in other species. In fact, the general structure of P2 in both stable and non-stable state (SS) forms are similar to that of the beta-amyloid protein of AD [6] [29]. Our results show that several proteins of this family exhibit mitogen-activated protein kinase (MAPK)-dependent conformational flexibility: for example, for P3 the interaction between the beta-sheet and the n-terminal metalloprotein was of intermediate length (average k A = 16.3–16.9 kDa), and the zinc finger-like domains are seen throughout the transition region, indicating that the extracellular domain is only partially closed (Table S2). Because these proteins are held in the aggregates in a periodicity of ~7 s, an additional key step is required to initiate protein–protein interactions: the protein-binding domain of pore water must bind to a protein in its intermolecular conformational landscape. This is done by the first important α-helix β-sheet interaction in the alpha helix, to which MAPK receptors are involved [30] and in which the peak k A is ~15 kDa.

	---------------------------

	THERESA:

	Coronaviruses. For my part, I actually didn't know anything about them, until the beginning of this very special year 2020. And then this year everything turned upside down and by now you have probably all heard enough of the latest coronavirus strain, SARS-CoV2. For those of you who spent the last months on Mars: SARS-CoV2 is the third strain of coronaviruses that recently expanded its range of host animals successfully to include humans and in this new host, us, can trigger serious respiratory diseases. The first two coronaviruses to “achieve” this were SARS-CoV, which triggered the first pandemic of the 21st century in 2002/03, and MERS-CoV, which is around since 2012. Of these three viruses, MERS-CoV appears to be the deadliest. However, since it rarely transmits from person to person, it spreads very slowly (although there is a very real danger that this could change at some point). The first (2003) SARS-CoV in many aspects is very similar to the current SARS-CoV2. They are surrounded by a fatty shell, which is why they can be easily destroyed by soap or disinfectant. The so-called spike proteins (shown in the image in red) sit in this fatty sheath and can bind to certain proteins on cell surfaces in order to allow the virus to penetrate the host cell membranes. Both SARS coronaviruses bind with their spike protein to the same surface proteins on our cells: ACE2 and TMPRSS2, whereby – after a few rounds of mutations - the new SARS-CoV2 binds to ACE2 with 10-20-fold higher affinity than the original SARS-Virus did. This contributes significantly to the new SARS-CoV2 being so particularly infectious. Both ACE2 and TMPRSS2 thus are currently being researched intensively. This is done primarily with regard to possible therapies that could target these proteins. In this article I will introduce you to the ACE2 protein, next week I will present you TMPRSS2.

	GPT-2:

	The ACE2 protein is the first protein encountered by the virus during cell-to-cell contact. It is however less likely to be targetted by immune cells in our body than most other proteins, for it is no longer protected from immune destruction by the body's immune system as it was in the original SARS-CoV1. Therefore its presence would be somewhat welcome - as might be the potential for a new anti-viral drug that is able to selectively target the infected cell. So let's first have a look at the protein of interest. As you can see, ACE2 consists of 26 amino acid residues arranged in two "chains" each of which comprises 12 amino acids. Thus the total ACE2 protein chain comprises 71 amino acids and requires the usage of one molecule (since any longer protein chain would be too long to fit into the cell's outer membrane, and because small chains of amino acids don't have an extremely high uptake by the cell membrane, although they would be very high-affinity for the virus's plasma membrane). This leads us to the next question - how is the ACE2 protein adapted to its new role? It is unlikely that there are many amino acids in the cell membrane, so if there are any left, they would probably have to be left over in one of the 3 folding steps in which the ACE2 proteins are folded into a given α/β complex. We'll take a look at each of these steps in turn and see what possible amino acids there are left.

	---------------------------