7bag
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | ==== | + | ==C3b in complex with CP40== |
| - | <StructureSection load='7bag' size='340' side='right'caption='[[7bag]]' scene=''> | + | <StructureSection load='7bag' size='340' side='right'caption='[[7bag]], [[Resolution|resolution]] 2.00Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7bag]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BAG FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7bag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bag OCA], [https://pdbe.org/7bag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bag RCSB], [https://www.ebi.ac.uk/pdbsum/7bag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bag ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACM:ACETAMIDE'>ACM</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene>, <scene name='pdbligand=EXL:1-Methyl-L-tryptophan'>EXL</scene>, <scene name='pdbligand=IML:N-METHYL-ISOLEUCINE'>IML</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SAR:SARCOSINE'>SAR</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7bag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bag OCA], [https://pdbe.org/7bag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bag RCSB], [https://www.ebi.ac.uk/pdbsum/7bag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bag ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:[https://omim.org/entry/613779 613779]. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis.<ref>PMID:19913840</ref> <ref>PMID:9596584</ref> <ref>PMID:11387479</ref> <ref>PMID:15713468</ref> <ref>PMID:7961791</ref> [:] Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:[https://omim.org/entry/611378 611378]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:19913840</ref> <ref>PMID:17634448</ref> Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:[https://omim.org/entry/612925 612925]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19913840</ref> <ref>PMID:18796626</ref> <ref>PMID:20513133</ref> Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.<ref>PMID:19913840</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref> Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref> Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-A resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs. | ||
| + | |||
| + | Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors.,Lamers C, Xue X, Smiesko M, van Son H, Wagner B, Berger N, Sfyroera G, Gros P, Lambris JD, Ricklin D Nat Commun. 2022 Sep 20;13(1):5519. doi: 10.1038/s41467-022-33003-7. PMID:36127336<ref>PMID:36127336</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7bag" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Complement C3 3D structures|Complement C3 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Synthetic construct]] |
| + | [[Category: Gros P]] | ||
| + | [[Category: Lambris J]] | ||
| + | [[Category: Lamers C]] | ||
| + | [[Category: Ricklin D]] | ||
| + | [[Category: Sfyroera G]] | ||
| + | [[Category: Smiesko M]] | ||
| + | [[Category: Wagner B]] | ||
| + | [[Category: Xue X]] | ||
| + | [[Category: Van Son H]] | ||
Revision as of 06:09, 2 March 2023
C3b in complex with CP40
| |||||||||||
Categories: Homo sapiens | Large Structures | Synthetic construct | Gros P | Lambris J | Lamers C | Ricklin D | Sfyroera G | Smiesko M | Wagner B | Xue X | Van Son H
