Publications by authors named "Che Lifan"

3 Publications

  • Page 1 of 1

Molecular conversion of MIG6 hotspot-3 peptide from the nonbinder to a moderate binder of HER2 by rational design of an orthogonal interaction system at the HER2-peptide interface.

Biophys Chem 2021 Sep 23;276:106625. Epub 2021 May 23.

Department of Obstetrics and Gynecology, Yidu Central Hospital Affiliated to Weifang Medical University, Weifang 262500, China. Electronic address:

Human epidermal growth factor receptor 2 (HER2) has been established as an approved druggable target for the treatment of patients with diverse gynecological tumors such as ovarian, cervical and breast cancers. The mitogen-inducible gene 6 (MIG6) protein is a negative regulator of HER2 signaling by using its Seg1 segment to disrupt the allosteric dimerization of HER2 kinase domain. Previous studies found that the Seg1 adopts three separated hotspots to interact with the HER2 dimerization interface, in which the third hotspot (H3) is located at the core region of the interface but its derived H3 peptide (PKYVS) and Tyr358Phe mutant (PKFVS) cannot bind effectively to the interface in an independent manner. In this study, we demonstrate that the H3 peptide can be converted from nonbinder to a moderate binder of HER2 by just adding an orthogonal noncovalent interaction system (X⋯O┄H) between a halogen bond (X⋯O) and a hydrogen bond (H┄O) involving peptide Phe358 residue and HER2 Val948/Trp951 residues. High-level calculations are utilized to rigorously characterize and rationally design the X⋯O┄H system, which is then optimized with different halogen atoms and at different substituting positions. It is revealed that there is a synergistic effect between the X⋯O and H┄O of the orthogonal interaction system; formation of the halogen bond can enhance the interaction strength of the hydrogen bond. In silico analysis and in vitro assay reach a consistence that Br-substitution at the m-position of peptide Phe358 phenyl moiety is the best choice that can render strong interaction for the X⋯O┄H system, which also makes the peptide 'bindable' to HER2 kinase domain, while F/Cl/I-substitution at the same position can only improve the peptide affinity moderately or modestly. In contrast, the Br-substitution at the o- and p-positions of peptide Phe358 phenyl moiety cannot define effective X⋯O┄H interaction and thus does not confer additional affinity to the HER2-peptide complex.
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September 2021

Revisiting bone morphogenetic protein-2 knuckle epitope and redesigning the epitope-derived peptides.

J Pept Sci 2021 Jun 22;27(6):e3309. Epub 2021 Feb 22.

Department of Orthopedics, Yidu Central Hospital Affiliated to Weifang Medical University, Weifang, China.

The bone morphogenetic protein-2 (BMP2) plays a crucial role in bone formation, growth and regeneration, which adopts a conformational wrist epitope and a linear knuckle epitope to interact with its type-I (BRI) and type-II (BRII) receptors, respectively. In this study, we systematically examine the BRII-recognition site of BMP2 at structural, energetic and dynamic levels and accurately locate hotspots of the recognition at BMP2-BRII complex interface. It is revealed that the traditional knuckle epitope (BMP2 residue range 73-92) do fully match the identified hotspots; the BMP2-recognition site includes the C-terminal region of traditional knuckle epitope as well as its flanked β-strands. In addition, the protein context of full-length BMP2 is also responsible for the recognition by addressing conformational constraint on the native epitope segment. Therefore, we herein redefine the knuckle epitope to BMP2 residue range 84-102, which has a similar sequence length but is slid along the protein sequence by ~10 residues as compared to traditional knuckle epitope. The redefined one is also a linear epitope that is natively a double-stranded β-sheet with two asymmetric arms as compared to the natively single β-strand of the traditional version, although their sequences are partially overlapped to each other. It is revealed that the redefined epitope-derived peptide LN exhibits an improved affinity by >3-fold relative to the traditional epitope-derived peptide KL . Even so, the LN peptide still cannot fully represent the BMP2 recognition event by BRII that has been reported to have a nanomolar affinity. We further introduce a disulfide bond across the two arms of double-stranded β-sheet to constrain the free LN peptide conformation, which mimics the conformational constraint addressed by protein context. Consequently, several cyclic peptides are redesigned, in which the LN (cyc89-101) is determined to exhibit a sub-micromolar affinity; this value is ~5-fold higher than its linear counterpart. Structural analysis also reveals that the cyclic peptide can interact with BRII in a similar binding mode with the redefined knuckle epitope region in full-length BMP2 protein.
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June 2021

Effect of carboprost tromethamine in prevention of postpartum hemorrhage in cesarean section.

Pak J Pharm Sci 2018 Sep;31(5(Special)):2257-2262

Obstetrics Department, Weifang YiDu Center Hospital, Qingzhou, China.

Carboprost tromethamine is a synthetic prostaglandin derivative, which can effectively promote law contraction of the uterus and significantly reduce the amount of bleeding during and after delivery. In this study, we explored the effect of carboprost tromethamine on the prevention of postpartum hemorrhage after cesarean section and the effect on coagulation function and hemodynamics. At the same time, the effects of oxytocin and carboprost tromethamine were studied in different groups. The results showed that the amount of 2h bleeding (256.7±65.21) mL and the amount of 24h hemorrhage (308.3±78.3) after the operation were significantly decreased, and the difference was statistically significant (P<0.05). After the operation, the levels of APTT, TT and Fib in the two groups were significantly lower than those before the operation. The levels of SBP (119.4±8.24) mmHg and DBP (79.6±6.21) mmHg in the experimental group were significantly higher than those of the control group. In summary, carboprost tromethamine has a significant effect on the prevention of postpartum hemorrhage in cesarean section, and has a significant effect on improving the state of hypercoagulable blood and maintaining the stable hemodynamic state, which has clinical a value.
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September 2018