D6: Structural Biology and Biophysics I – 22827 (Fall 2022)
D7: Structural Biology and Biophysics II – 24284 (Spring 2023)
(2 hrs/week; 1 CP)
Stephan Grzesiek, Sebastian Hiller, Rod Lim, Timm Maier
The Structural Biology and Biophysics Seminar series (SBBS) is organized by PhD students of the Biozentrum, University of Basel since 2009. World-leading scientists are invited to present their current work to an audience of students, researchers and PIs. Typical lectures in this series describe applications of advanced structural biology and biophysics methods to solve biological problems. Methods include NMR spectroscopy, X-ray crystallography, cryo-electron microscopy, surface plasmon resonance and atomic force microscopy, but not only. The list of the past SBBS speakers is accessible here.
The talks take place on Tuesdays, the time will depend on speaker, room U1.197
The Fall Semester 2022 Program will be available soon. Unless mentioned, attendance is open to all interested people, without registration.
September 27th, 2022 at 12:15
SBBS introductory meeting for students
October 18th, 2022 at 12:15, room U1.197
Title: Uptake mechanism of essential omega-3 fatty acids into the brain and inhibition by an endogenous retroviral element
The Central Nervous System (CNS) requires uptake of essential omega-3 fatty acids in the form of lysophospholipids for normal development and cognitive function, and this is achieved by major-facilitator superfamily transporter MFSD2A expressed at the brain-blood barrier (BBB). MFSD2A-mediated lipid uptake is key to maintain low rates of solute transport across the BBB, and has emerged as a point of potential pharmacological intervention to aid therapeutic-drug delivery into the CNS.
MFSD2A plays a second important function in human physiology, as receptor of retrovirus-derived envelope protein syncytin 2 (SYNC2), and MFSD2A-SYNC2 complexes mediate cell-cell fusion and formation of the maternal-fetal interface in placenta.
During my seminar, I will discuss recent structural and functional work from my lab on the lipid-transport and receptor molecular mechanisms of human MFSD2A, as well as the potential pharmacological implications of those functions.
Prof. Nicolas Reyes
October 25th, 2022 at 12:15, room U1.197
Title: Structural insights into U1 snRNP recruitment during co-transcriptional splicing
Gene expression in eukaryotes requires synthesis of pre-mRNA by RNA polymerase II (Pol II) and processing such as splicing to produce mature mRNA. During splicing, introns are removed in a co-transcriptional manner as the nascent RNA emerges from the Pol II surface. Co-transcriptional splicing enhances the efficiency and accuracy of pre-mRNA processing and begins with the recruitment of the U1 small nuclear ribonucleoprotein (U1 snRNP) to the 5´ splice site of pre-mRNA. Here we present the cryo-EM structure of a mammalian transcribing Pol II-U1 snRNP complex that revealed the molecular basis of a direct interaction between the transcription and splicing machineries. This interaction positions the 5´ splice site near the RNA exit site of Pol II. Retention of the 5´ splice site near the Pol II surface leads to formation of a growing intron loop as pre-mRNA is extended, facilitating functional pairing of distant intron ends and spliceosome assembly on the Pol II surface. Our results provide a starting point for a mechanistic analysis of co-transcriptional splicing.
November 15th, 2022 at 12:15, room U1.197
Title: Of protein allostery and automated structure determination by NMR
Despite its essential role in the activity of proteins, the protein structural landscape with its multiple states and the dynamic exchange between them is still not well-studied. With recent method developments in solution state NMR yielding highly accurate time averaged distance restraints the multiple states can be elucidated at atomic resolution as presented for the enzyme cyclophilin, The allosteric WW domain of PIN1 and a PDZ domain giving insights into the origin of correlated motion and protein allostery. Further analysis indicate that correlated states are observable in standard NMR structures opening an avenue towards a comprehensive understanding and elucidation of protein motion at atomic resolution with predictive power. Automated NMR structure determination demonstrated with the software package ARTINA is thereby regarded a helpful contribution.
Prof. Roland Riek
November 22th, 2022 at 12:15, by Zoom
Title: Predicting protein-protein interactions using AlphaFold
Zoom link: https://unibas.zoom.us/j/65662810834
AlphaFold can predict the structure of single- and multiple-chain proteins with very high accuracy. However, the accuracy decreases with the number of chains, and the available GPU memory limits the size of protein complexes which can be predicted. Here we show that one can predict the structure of large complexes starting from predictions of subcomponents. Using Monte Carlo tree search, we assemble 91 out of 175 complexes with 10-30 chains from predicted subcomponents, with a median TM-score of 0.51. There are 30 highly accurate complexes (TM-score ≥0.8, 33% of complete assemblies). We create a scoring function, mpDockQ, that can distinguish if assemblies are complete and predict their accuracy. We find that complexes containing symmetry are accurately assembled, while asymmetrical complexes remain challenging. The method is freely available and accessible as a Colab notebook https://colab.research.google.com/github/patrickbryant1/MoLPC/blob/master/MoLPC.ipynb.
November 29th, 2022 at 12:15, room U1.197
Title: Unlocking the molecular mechanism of glycine transport and inhibition
Glycine transporter GlyT1 is the main regulator of neuronal excitation and inhibition mediated by neurotransmitter glycine in the brain. Prolonging glycinergic signalling through selective inhibition of GlyT1 has been pursued extensively over the past two decades as a key strategy for the treatment of a broad range of neurological/psychiatric disorders including schizophrenia. GlyT1 inhibitors achieve antipsychotic and pro-cognitive effects against many symptoms of schizophrenia, however a successful drug candidate has to come. To elucidate structure-based mechanisms for inhibition and transport in GlyT1, we have investigated its complexes with a benzoylpiperazine chemotype inhibitor and substrate glycine. Using an inhibition state-specific sybody and a serial synchrotron crystallography (SSX) approach, we have determined the structure of GlyT1 at 3.4 Å resolution to reveal the selective inhibitor-bound state, adopting an inward-open conformation. More recently, we have determined the cryo-electron microscopy (cryo-EM) structure of GlyT1 at 3.3 Å resolution showing the glycine-bound inward-facing occluded conformation. The data unveil a dual nature of non-competitive inhibitors of functional transport exhibiting also competitive binding to the substrate binding site of glycine. The results provide detailed insight into the mechanism of glycine transport and reuptake inhibition and help re-evaluate efforts for the development of efficacious GlyT1 inhibitors.
December 13th, 2022 at 12:15, room U1.197
Title: Approaches to designing protein folds and functions
Protein design aims to build new proteins with novel functions. Methods range from generating and screening of mutant libraries via repurposing of active sites or binding pockets all the way to de novo design. In many of these approaches protein structures form the basis for the designs and structures are solved to validate the hypotheses. I will discuss the advantages and difficulties of the different approaches and show some highlights from our recent applications that range from the repurposing of a repressor to a plant sensor via evolution-guided design by chimeragenesis to the de novo design of TIM-barrel proteins. However, protein design is changing tremendously with the rapidly developing Ai-based methods. Based on the similarity of protein sequences and language, we started working with a natural language model. Here I will talk about our experiences and current results with this new technology.
Important information for students enrolled at the University of Basel:
- You can earn one credit point (CP) by registering to the course.
- To get the CP for this course, all of the proposed seminars have to be attended from start to finish and a written exam in the form of an essay must be passed.
- It is your responsibility to check this website for eventual updates/changes to the program.
- Each in-person seminar is followed by a lunch with the speaker. Contact the host if you are interested in participating.