Small-molecule modulation of protein-protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under-represented. Here, we report the example of a semi-synthetic natural product derivative--ISIR-005--that stabilizes the cancer-relevant interaction of the adaptor protein 14-3-3 and Gab2. The crystal structure of ISIR-005 in complex with 14-3-3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim-of-the-interface of the protein complex. Only in the direct vicinity of 14-3-3/Gab2pT391 site is a pre-formed pocket occupied by ISIR-005; binding of the Gab2pS210 motif to 14-3-3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR-005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14-3-3/Gab2 PPI interface with important implications for the development of PPI stabilizers.

No abstract

Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.

Summary Background and objectives Convolutional neural networks (CNN) enable accurate diagnosis of medical images and perform on or above the level of individual physicians. Recently, collective human intelligence (CoHI) was shown to exceed the diagnostic accuracy of individuals. Thus, diagnostic performance of CoHI (120 dermatologists) versus individual dermatologists versus two state‐of‐the‐art CNN was investigated. Patients and Methods Cross‐sectional reader study with presentation of 30 clinical cases to 120 dermatologists. Six diagnoses were offered and votes collected via remote voting devices (quizzbox®, Quizzbox Solutions GmbH, Stuttgart, Germany). Dermatoscopic images were classified by a binary and multiclass CNN (FotoFinder Systems GmbH, Bad Birnbach, Germany). Three sets of diagnostic classifications were scored against ground truth: (1) CoHI, (2) individual dermatologists, and (3) CNN. Results CoHI attained a significantly higher accuracy [95 % confidence interval] (80.0 % [62.7 %–90.5 %]) than individual dermatologists (75.7 % [73.8 %–77.5 %]) and CNN (70.0 % [52.1 %–83.3 %]; all P < 0.001) in binary classifications. Moreover, CoHI achieved a higher sensitivity (82.4 % [59.0 %–93.8 %]) and specificity (76.9 % [49.7 %–91.8 %]) than individual dermatologists (sensitivity 77.8 % [75.3 %–80.2 %], specificity 73.0 % [70.6 %–75.4 %]) and CNN (sensitivity 70.6 % [46.9 %–86.7 %], specificity 69.2 % [42.4 %–87.3 %]). The diagnostic accuracy of CoHI was superior to that of individual dermatologists (P < 0.001) in multiclass evaluation, with the accuracy of the latter comparable to multiclass CNN. Conclusions Our analysis revealed that the majority vote of an interconnected group of dermatologists (CoHI) outperformed individuals and CNN in a demanding skin lesion classification task.