Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin. To explore the molecular basis for this selectivity, we synthesized and tested novel C5/C6-derivatives designed from quantum-based modeling of the interactions revealed in the co-crystal structures of PP5C in complex with cantharidin. Structure–activity relationship studies and analysis of high-resolution (1.25 Å) PP5C-inhibitor co-crystal structures reveal close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, the latter of which is substituted by tryptophan in PP4C. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain in PP4C would force all cantharidin-based inhibitors into an unfavorable binding mode, disrupting the strong coordination of active site metal ions observed in the PP5C co-crystal structures, thereby rendering PP4C insensitive to the inhibitors. This prediction was confirmed by inhibition studies employing native human PP4C. Mutation of PP5C (F446W) and PP1C (F257W), to mimic the PP4C active site, resulted in markedly suppressed sensitivity to cantharidin. These observations provide insight into the structural basis for the natural selectivity of cantharidin and provide an avenue for PP4C deselection. The novel crystal structures also provide insight into interactions that provide increased selectivity of the C5/C6 modifications for PP5C versus other PPP-family phosphatases.
Background
As globalization of surgical training increases, growing evidence demonstrates a positive impact of global surgery experiences on trainees from high-income countries (HIC). However, few studies have assessed the impact of these largely unidirectional experiences from the perspectives of host surgical personnel from low- and middle-income countries (LMIC). This study aimed to assess the impact of unidirectional visitor involvement from the perspectives of host surgical personnel in Kijabe, Kenya.
Methods
Voluntary semi-structured interviews were conducted with 43 host surgical personnel at a tertiary referral hospital in Kijabe, Kenya. Qualitative analysis was used to identify salient and recurring themes related to host experiences with visiting surgical personnel. Perceived benefits and challenges of HIC involvement and host interest in bidirectional exchange were assessed.
Results
Benefits of visitor involvement included positive learning experiences (95.3%), capacity building (83.7%), exposure to diverse practices and perspectives (74.4%), improved work ethic (51.2%), shared workload (44.2%), access to resources (41.9%), visitor contributions to patient care (41.9%), and mentorship opportunities (37.2%). Challenges included short stays (86.0%), visitor adaptation and integration (83.7%), cultural differences (67.4%), visitors with problematic behaviors (53.5%), learner saturation (34.9%), language barriers (32.6%), and perceived power imbalances between HIC and LMIC personnel (27.9%). Nearly half of host participants expressed concerns about the lack of balanced exchange between HIC and LMIC programs (48.8%). Almost all (96.9%) host trainees expressed interest in a bidirectional exchange program.
Conclusion
As the field of global surgery continues to evolve, further assessment and representation of host perspectives is necessary to identify and address challenges and promote equitable, mutually beneficial partnerships between surgical programs in HIC and LMIC.
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