PMID- 37909467
OWN - NLM
STAT- Publisher
LR  - 20231101
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
DP  - 2023 Nov 1
TI  - Dynamics simulation, energetics calculation and experimental analysis of the 
      intermolecular interaction between human neonatal ABL SH3 domain and its 
      N-substituted peptoid ligands.
PG  - 1-8
LID - 10.1080/07391102.2023.2272344 [doi]
AB  - Non-receptor tyrosine kinase of neonatal ABL (nABL) is distributed in the nucleus 
      and cytoplasm of proliferating cells in embryo and neonate, and has been 
      implicated in the pathogenesis of neonatal leukemia and other hematological 
      diseases. The kinase contains a regulatory Src homology 3 (SH3) domain that can 
      specifically recognize proline-rich peptide segments on its partner protein 
      surface. In this study, we systematically investigated the N-substitution effect 
      on the binding of an empirically designed proline-rich peptide p9 to nABL SH3 
      domain by integrating dynamics simulations, energetics calculations and 
      fluorescence affinity assays. The p9 is an almost all proline-composed 
      decapeptide, with only a sole tyrosine at its residue 4, which has been found to 
      bind nABL SH3 domain at a micromolar level in a class I mode. Here, the non-key 
      residues of p9 peptide were independently replaced by various N-substituted amino 
      acids to create a systematic N-substitution profile, from which we can identify 
      those favorable, neutral and unfavorable substitutions at each peptide residue. 
      On this basis a combinatorial peptoid library was rationally designed by 
      systematically combining the favorable N-substituted amino acids at non-key 
      residues of p9 peptide, thus resulting in a number of its peptoid counterparts. 
      The binding affinity of top peptoid hits was observed to be comparable with or 
      improved moderately relative to p9 peptide, with K(d) ranging between 3.1 and 
      76 muM. Structural analysis revealed that the peptoids can be divided into 
      exposed, polar and hydrophobic regions from N- to C-termini, in which the polar 
      and hydrophobic regions confer specificity and stability to the domain-peptoid 
      interaction, respectively. In addition, a designed peptoid was also observed to 
      exhibit 5.3-fold SH3-selectivity for nABL over cSRC, suggesting that the 
      N-substitution can be used to improve not only binding affinity but also 
      recognition specificity of SH3 binders.Communicated by Ramaswamy H. Sarma.
FAU - Zhao, Shijian
AU  - Zhao S
AD  - Department of Gynaecology and Obstetrics, Suzhou Kowloon Hospital, Shanghai Jiao 
      Tong University School of Medicine, Suzhou, China.
FAU - Shen, Lili
AU  - Shen L
AD  - Department of Pediatrics, Suzhou Kowloon Hospital, Shanghai Jiao Tong University 
      School of Medicine, Suzhou, China.
FAU - Wang, Qiuqin
AU  - Wang Q
AD  - School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Lu, Wenxiao
AU  - Lu W
AD  - Department of Gynaecology and Obstetrics, Suzhou Kowloon Hospital, Shanghai Jiao 
      Tong University School of Medicine, Suzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20231101
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
SB  - IM
OTO - NOTNLM
OT  - N-substituted amino acid
OT  - SH3 domain
OT  - molecular design
OT  - molecular dynamics
OT  - neonatal ABL kinase
OT  - peptide
OT  - peptoid
EDAT- 2023/11/01 12:44
MHDA- 2023/11/01 12:44
CRDT- 2023/11/01 07:43
PHST- 2023/11/01 12:44 [medline]
PHST- 2023/11/01 12:44 [pubmed]
PHST- 2023/11/01 07:43 [entrez]
AID - 10.1080/07391102.2023.2272344 [doi]
PST - aheadofprint
SO  - J Biomol Struct Dyn. 2023 Nov 1:1-8. doi: 10.1080/07391102.2023.2272344.