5xn3
Crystal structure of SPSB2 in complex with a rational designed RGD containing cyclic peptide inhibitor of SPSB2-iNOS interaction
Structural highlights
FunctionSPSB2_HUMAN Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.[1] Publication Abstract from PubMedSPRY 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 Kd of 671 nM, and saturation transfer difference NMR showed that cR8 binds to alphavbeta3 integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 A. 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. Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.,You T, Wang Y, Li K, Zhang D, Wei H, Luo Y, Li H, Lu Y, Su X, Kuang Z Biochem Biophys Res Commun. 2017 Jul 29;489(3):346-352. doi:, 10.1016/j.bbrc.2017.05.122. Epub 2017 May 24. PMID:28549582[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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