Structural Insights into RNA Recognition by RIG-I

Steroid hormone synthesis in mitochondria.

Altering the specificity of an enzyme requires precise positioning of side-chain functional groups that interact with the modified groups of the new substrate. This requires not only sequence changes that introduce the new functional groups but also sequence changes that remodel the structure of the protein backbone so that the functional groups are properly positioned. We describe a computational design method for introducing specific enzyme-substrate interactions by directed remodeling of loops near the active site. Benchmark tests on 8 native protein-ligand complexes show that the method can recover native loop lengths and, often, native loop conformations. We then use the method to redesign a critical loop in human guanine deaminase such that a key side-chain interaction is made with the substrate ammelide. The redesigned enzyme is 100-fold more active on ammelide and 2.5e4-fold less active on guanine than wild-type enzyme: The net change in specificity is 2.5e6-fold. The structure of the designed protein was confirmed by X-ray crystallographic analysis: The remodeled loop adopts a conformation that is within 1-A Calpha RMSD of the computational model.

https://www.pnas.org/content/pnas/106/23/9215.full.pdf

Alteration of enzyme specificity by computational loop remodeling and design.

https://www.gastrojournal.org/article/S0016-5085(10)01883-4/pdf

Inosine Triphosphate Protects Against Ribavirin-Induced Adenosine Triphosphate Loss by Adenylosuccinate Synthase Function

Background 
Dengue fever is an increasingly significant arthropod-borne viral disease, with at least 50 million cases per year worldwide. As with other viral pathogens, dengue virus is dependent on its host to perform the bulk of functions necessary for viral survival and replication. To be successful, dengue must manipulate host cell biological processes towards its own ends, while avoiding elimination by the immune system. Protein-protein interactions between the virus and its host are one avenue through which dengue can connect and exploit these host cellular pathways and processes.


Methodology/Principal Findings 
We implemented a computational approach to predict interactions between Dengue virus (DENV) and both of its hosts, Homo sapiens and the insect vector Aedes aegypti. Our approach is based on structural similarity between DENV and host proteins and incorporates knowledge from the literature to further support a subset of the predictions. We predict over 4,000 interactions between DENV and humans, as well as 176 interactions between DENV and A. aegypti. Additional filtering based on shared Gene Ontology cellular component annotation reduced the number of predictions to approximately 2,000 for humans and 18 for A. aegypti. Of 19 experimentally validated interactions between DENV and humans extracted from the literature, this method was able to predict nearly half (9). Additional predictions suggest specific interactions between virus and host proteins relevant to interferon signaling, transcriptional regulation, stress, and the unfolded protein response.


Conclusions/Significance 
Dengue virus manipulates cellular processes to its advantage through specific interactions with the host's protein interaction network. The interaction networks presented here provide a set of hypothesis for further experimental investigation into the DENV life cycle as well as potential therapeutic targets.

/pdf/mapping-protein-interactions-between-dengue-virus-and-its-3qhtuqq7ue.pdf

Mapping Protein Interactions between Dengue Virus and Its Human and Insect Hosts

Crystal structure of VEGFR1 in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benzamide

Human steroidogenic acute regulatory protein

Human adenylosuccinate lyase in complex with its substrate N6-(1,2- Dicarboxyethyl)-AMP, and its products AMP and fumarate.

PDB ID : 2OJW Title : Crystal structure of human glutamine synthetase in complex with ADP and phosphate Authors : Karlberg, T.; Uppenberg, J.; Arrowsmith, C.; Berglund, H.; Busam, R.D.; Collins, R.; Edwards, A.; Flodin, S.; Flores, A.; Graslund, S.; Hallberg, B.M.; Hammarstrom, M.; Hogbom, M.; Johansson, I.; Kotenyova, T.; Moche, M.; Nilsson, M.E.; Nordlund, P.; Nyman, T.; Ogg, D.; Persson, C.; Sagemark, J.; Stenmark, P.; Sundstrom, M.; Thorsell, A.G.; Van Den Berg, S.; Wallden, K.; Weigelt, J.; Holmberg-Schiavone, L.; Structural Genomics Consortium (SGC) Deposited on : 2007-01-15 Resolution : 2.05 Å(reported)

T. Nyman

Papers

Crystal structure of VEGFR1 in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benzamide

Human steroidogenic acute regulatory protein

Human adenylosuccinate lyase in complex with its substrate N6-(1,2- Dicarboxyethyl)-AMP, and its products AMP and fumarate.

Crystal structure of human glutamine synthetase in complex with ADP and phosphate

S-adenosyl homocysteine hydrolase (SAHH) from Trypanosoma brucei