6dn8: Difference between revisions
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==SPRY domain-containing SOCS box protein 2 complexed with (GZJ)VDINNN(CY3) Cyclic peptide inhibitor== | |||
<StructureSection load='6dn8' size='340' side='right'caption='[[6dn8]], [[Resolution|resolution]] 1.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6dn8]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DN8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DN8 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CY3:2-AMINO-3-MERCAPTO-PROPIONAMIDE'>CY3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=GZJ:'>GZJ</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dn8 OCA], [http://pdbe.org/6dn8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dn8 RCSB], [http://www.ebi.ac.uk/pdbsum/6dn8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dn8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/SPSB4_HUMAN SPSB4_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.<ref>PMID:15601820</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design. | |||
A Cyclic Peptide Inhibitor of the iNOS-SPSB Protein-Protein Interaction as a Potential Anti-Infective Agent.,Sadek MM, Barlow N, Leung EWW, Williams-Noonan BJ, Yap BK, Shariff FM, Caradoc-Davies TT, Nicholson SE, Chalmers DK, Thompson PE, Law RHP, Norton RS ACS Chem Biol. 2018 Oct 19;13(10):2930-2938. doi: 10.1021/acschembio.8b00561., Epub 2018 Sep 18. PMID:30226743<ref>PMID:30226743</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6dn8" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Caradoc-Davies, T T]] | |||
[[Category: Law, R H.P]] | |||
[[Category: Norton, R S]] | |||
[[Category: Immune system]] | |||
[[Category: Immune system-inhibitor complex]] | |||
[[Category: Inhibitor]] | |||
[[Category: Nitric oxide]] | |||
[[Category: Proteasomal degradation]] | |||
Revision as of 08:54, 17 April 2019
SPRY domain-containing SOCS box protein 2 complexed with (GZJ)VDINNN(CY3) Cyclic peptide inhibitorSPRY domain-containing SOCS box protein 2 complexed with (GZJ)VDINNN(CY3) Cyclic peptide inhibitor
Structural highlights
Function[SPSB4_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- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design. A Cyclic Peptide Inhibitor of the iNOS-SPSB Protein-Protein Interaction as a Potential Anti-Infective Agent.,Sadek MM, Barlow N, Leung EWW, Williams-Noonan BJ, Yap BK, Shariff FM, Caradoc-Davies TT, Nicholson SE, Chalmers DK, Thompson PE, Law RHP, Norton RS ACS Chem Biol. 2018 Oct 19;13(10):2930-2938. doi: 10.1021/acschembio.8b00561., Epub 2018 Sep 18. PMID:30226743[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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