5XN3

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

Summary for 5XN3

• Entry DOI: 10.2210/pdb5xn3/pdb
• Related PRD ID: PRD_002275
• Descriptor: SPRY domain-containing SOCS box protein 2, cR8 peptide from NOS2 (3 entities in total)
• Functional Keywords: e3 ubiquitin, ligase, cyclic peptide inhibitor, spry domain-containing, socs box protein, inducible nitric oxide synthase, nitric oxide, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : Q99619
• Total number of polymer chains: 2
• Total formula weight: 23798.55

Authors

You, T.,Kuang, Z. (deposition date: 2017-05-17, release date: 2017-06-14, Last modification date: 2024-11-13)

Primary citation

You, T.,Wang, Y.,Li, K.,Zhang, D.,Wei, H.,Luo, Y.,Li, H.,Lu, Y.,Su, X.,Kuang, Z.
Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.
Biochem. Biophys. Res. Commun., 489:346-352, 2017

PubMed 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 of 671 nM, and saturation transfer difference NMR showed that cR8 binds to αβ 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.

PubMed: 28549582
DOI: 10.1016/j.bbrc.2017.05.122

Experimental method

X-RAY DIFFRACTION (1.34 Å)