| 1. |
- Chakrabarti, Kalyan S., et al.
(författare)
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A litmus test for classifying recognition mechanisms of transiently binding proteins
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks.
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| 2. |
- Erdelyi, Mate, 1975, et al.
(författare)
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Dynamics of the Glycosidic Linkage: Conformational Space of Lactose
- 2011
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Ingår i: Chemistry - A European Journal. - : Wiley. - 1521-3765 .- 0947-6539. ; 17:34, s. 9280-9282
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The dynamics of the glycosidic bond of lactose was studied by a paramagnetic tagging-based NMR technique, which allowed the collection of an unusually large series of NMR data for a single compound. By the use of distance- and orientation-dependent residual dipolar couplings and pseudocontact shifts, the simultaneous fitting of the probabilities of computed conformations and the orientation of the magnetic susceptibility tensor of a series of lanthanide complexes of lactose show that its glycosidic bond samples syn/syn, anti/syn and syn/anti f/y regions of the conformational space in water. The analysis indicates a higher reliability of pseudocontact shift data as compared to residual dipolar couplings with the presently available weakly orienting paramagnetic tagging technique. The method presented herein allows for an improved understanding of the dynamic behaviour of oligosaccharides.
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| 3. |
- Illini, Oliver, et al.
(författare)
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Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade >= 3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naive patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
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| 4. |
- Lind, Jesper, 1974-
(författare)
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Biophysical studies of membrane associated peptides
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A large part of the processes in living organisms involves proteins acting in a biological membrane. Biophysical studies on isolated model systems can give important understandings of the complicated biological mechanisms in the membrane. In this thesis peptide membrane interaction mechanisms are studied in several different systems. The membrane interactions of the unstructured endogenous opioid peptides dynorphinA (DynA) and dynorphinB (DynB) were investigated with Saturation Transfer Difference (STD) experiments, supplemented by various other NMR methods. The combined results support a conclusion that DynA binds to the lipid bilayer with the N-terminal residues inserted into the hydrophobic region and the C-terminal residues more loosely attached to the surface, while DynB is situated parallel to the bilayer. This difference in membrane interaction can explain observations that DynA has membrane perturbing effects while DynB has not. In the second study the binding domain of the glycosyltransferase A.laidlawii Monoglycosyldiacyl Glycerol Synthase (alMGS) was predicted and investigated mainly with NMR which enabled the determination of the 3D structure and position in a lipid environment. The phospholipid bilayers induce a large amphipathic α-helical content in the peptide, which aligns parallel but slightly tilted along the lipid surface with the N-terminus situated closer to the hydrophobic region. Lipid perturbation effects caused by peptide-membrane interactions were investigated by studying the influence of model transmembrane peptides on lipid dynamics in phospholipid bicelles with varying bilayer thickness. 13C-relaxation NMR of the lipids was used to survey the effects of the model peptides on the lipid bilayer.In paper IV and V structure and membrane interaction properties of the highly charged and flexible helix-turn-helix motif named the 'voltage sensor paddle' from two transmebrane voltage gated potassium channels was investigated. In membrane mimetic media, the KvaP paddle adopts the same type of helix-turn-helix conformation which can be seen in the Xray structure of the entire ion channel. The membrane interaction of the paddle HsapBK was compared with the corresponding one in KvaP, and both were inserted in the lipid bilayer but perturbed the lipid system differently, which may indicate differences in their function. Paper VI treats the structure of the novel site-specific fluorophore ReAsH bound to an optimized peptide sequence. The analysis shows that the important peptide mid segment configuration of CCPGCC is optimal for the ReAsH binding and that the N-terminal Phe1 plays an important role for the fluorophore process.
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| 5. |
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| 6. |
- Schleucher, Jürgen, et al.
(författare)
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TOCSY in ROESY and ROESY in TOCSY
- 2010
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Ingår i: Multidimensional NMR methods for the solution state. - : John Wiley & Sons. - 9780470770757 ; , s. 259-276
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 7. |
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| 8. |
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| 9. |
- Yamamoto, Sayoko, et al.
(författare)
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Paramagnetic lanthanide tagging for NMR conformational analyses of N-linked oligosaccharides.
- 2011
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 17:34, s. 9280-2
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Tidskriftsartikel (refereegranskat)abstract
- Sweet measurement: Paramagnetic tags are proposed as new tools for NMR analyses of carbohydrate conformations. A newly designed, lanthanide‐chelating tag can be attached to the common disaccharide core shared among all N‐linked oligosaccharides (see figure) and thereby provide reliable information on the glycosidic‐linkage conformation. This success opens the door to conformational studies of a variety of sugar chains of biological interest.
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