Cited by 20Biochemical and Structural CharacterizationReceptor Mechanisms and SignalingCytokine Signaling Pathways and Interactions

Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction

You, Tingting, Wang, Yuhui, Li, Kefa, Zhang, Danting, Wei, Huan, Luo, Yanhong, Li, Hua, Lu, Yongzhi +2 more·2017·Biochemical and Biophysical Research Communications

Abstract

SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV). ITC and chemical shift perturbation showed that cR8 binds to the iNOS binding site on SPSB2 with a K d of 671 nM, and saturation transfer difference NMR showed that cR8 binds to α v β 3 integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 Å. cR8 forms extensive hydrogen bonding with SPSB2 residues, but loss of an intramolecular hydrogen bond that is present in SPSB2-bound iNOS peptide may destabilize the bound conformation of cR8 and lead to a gentle reduction in SPSB2 binding affinity. These results serve as a useful basis for designing site-directed SPSB2 inhibitors in the future.

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Crossref · 10.1016/j.bbrc.2017.05.122

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  • A substrate-derived cyclic peptide targets a shallow site at the surface of the SPSB2 SPRY domain.

    “A substrate-derived cyclic peptide targets a shallow site at the surface of the SPSB2 SPRY domain 134 .”

    From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [134]

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Authors
You, T., Wang, Y., Li, K., Zhang, D., Wei, H., Luo, Y., Li, H., Lu, Y., Su, X., & Kuang, Z.
Affiliations
  • Jinan University (CN)
  • Chinese Academy of Sciences (CN)
  • Nankai University (CN)
Corresponding author
Kuang, Zhihe
Venue
Biochemical and Biophysical Research Communications
Publisher
Elsevier BV
Published
2017-07
Volume
489
Issue
3
Pages
346-352
ISSN
0006-291X (ISSN-L)
OpenAlex
W2619537023
Cited by
19
References
36
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 1
FWCI
1.34
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemical and Biophysical Research Communications (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (31270817, 81571539)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
inducible nitric oxide synthase, RGD peptide, cyclic peptide inhibitors, protein-protein interaction inhibition, crystal structure, integrin αvβ3, nitric oxide production, intramolecular hydrogen bonding, binding affinity
MeSH terms
Crystallization, Crystallography, Humans, Models, Molecular, Molecular Conformation, Oligopeptides, Peptides, Cyclic, Protein Binding, Structure-Activity Relationship, Drug Design, Suppressor of Cytokine Signaling Proteins, Nitric Oxide Synthase Type II

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