2zpx

From Proteopedia

(Difference between revisions)

Current revision

TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity; R1antTNF-T8

Structural highlights

2zpx is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.83Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TNFA_HUMAN Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).

Function

TNFA_HUMAN Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.^[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Tumour necrosis factor (TNF) is an important cytokine that induces an inflammatory response predominantly through the TNF receptor-1 (TNFR1). A crucial strategy for the treatment of many autoimmune diseases, therefore, is to block the binding of TNF to TNFR1. We previously identified a TNFR1-selective antagonistic mutant TNF (R1antTNF) from a phage library containing six randomized amino acid residues at the receptor-binding site (amino acids 84-89). Two R1antTNFs, R1antTNF-T2 (A84S, V85T, S86T, Y87H, Q88N and T89Q) and R1antTNF-T8 (A84T, V85P, S86A, Y87I, Q88N and T89R), were successfully isolated from this library. Here, we analysed R1antTNF-T8 using surface plasmon resonance spectroscopy and X-ray crystallography to determine the mechanism underlying the antagonistic activity of R1antTNF. The kinetic association/dissociation parameters of R1antTNF-T8 were higher than those of wild-type TNF, indicating more rapid bond dissociation. X-ray crystallographic analysis suggested that the binding mode of the T89R mutation changed from a hydrophobic to an electrostatic interaction, which may be responsible for the antagonistic behaviour of R1antTNF. Knowledge of these structure-function relationships will facilitate the design of novel TNF inhibitors based on the cytokine structure.

Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists.,Mukai Y, Nakamura T, Yoshioka Y, Shibata H, Abe Y, Nomura T, Taniai M, Ohta T, Nakagawa S, Tsunoda S, Kamada H, Yamagata Y, Tsutsumi Y J Biochem. 2009 Aug;146(2):167-72. Epub 2009 Apr 22. PMID:19386778^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
↑ Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
↑ Mukai Y, Nakamura T, Yoshioka Y, Shibata H, Abe Y, Nomura T, Taniai M, Ohta T, Nakagawa S, Tsunoda S, Kamada H, Yamagata Y, Tsutsumi Y. Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists. J Biochem. 2009 Aug;146(2):167-72. Epub 2009 Apr 22. PMID:19386778 doi:10.1093/jb/mvp065

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zpx"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_2zpx|  PDB=2zpx  |  SCENE=  }}
-===TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity; R1antTNF-T8===
-{{ABSTRACT_PUBMED_19386778}}
-==Disease==
+==TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity; R1antTNF-T8==
-[[http://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN]] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[http://omim.org/entry/607507 607507]]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).
+<StructureSection load='2zpx' size='340' side='right'caption='[[2zpx]], [[Resolution|resolution]] 2.83&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2zpx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZPX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZPX FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.83&#8491;</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=2zpx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zpx OCA], [https://pdbe.org/2zpx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zpx RCSB], [https://www.ebi.ac.uk/pdbsum/2zpx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zpx ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[https://omim.org/entry/607507 607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).
+== Function ==
+[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.<ref>PMID:16829952</ref>   The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.<ref>PMID:16829952</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zp/2zpx_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2zpx ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Tumour necrosis factor (TNF) is an important cytokine that induces an inflammatory response predominantly through the TNF receptor-1 (TNFR1). A crucial strategy for the treatment of many autoimmune diseases, therefore, is to block the binding of TNF to TNFR1. We previously identified a TNFR1-selective antagonistic mutant TNF (R1antTNF) from a phage library containing six randomized amino acid residues at the receptor-binding site (amino acids 84-89). Two R1antTNFs, R1antTNF-T2 (A84S, V85T, S86T, Y87H, Q88N and T89Q) and R1antTNF-T8 (A84T, V85P, S86A, Y87I, Q88N and T89R), were successfully isolated from this library. Here, we analysed R1antTNF-T8 using surface plasmon resonance spectroscopy and X-ray crystallography to determine the mechanism underlying the antagonistic activity of R1antTNF. The kinetic association/dissociation parameters of R1antTNF-T8 were higher than those of wild-type TNF, indicating more rapid bond dissociation. X-ray crystallographic analysis suggested that the binding mode of the T89R mutation changed from a hydrophobic to an electrostatic interaction, which may be responsible for the antagonistic behaviour of R1antTNF. Knowledge of these structure-function relationships will facilitate the design of novel TNF inhibitors based on the cytokine structure.
-==Function==
+Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists.,Mukai Y, Nakamura T, Yoshioka Y, Shibata H, Abe Y, Nomura T, Taniai M, Ohta T, Nakagawa S, Tsunoda S, Kamada H, Yamagata Y, Tsutsumi Y J Biochem. 2009 Aug;146(2):167-72. Epub 2009 Apr 22. PMID:19386778<ref>PMID:19386778</ref>
-[[http://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN]] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.<ref>PMID:16829952</ref>  The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.<ref>PMID:16829952</ref>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[2zpx]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZPX OCA].
+</div>
+<div class="pdbe-citations 2zpx" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-<ref group="xtra">PMID:019386778</ref><references group="xtra"/><references/>
+*[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Mukai, Y.]]
+[[Category: Large Structures]]
-[[Category: Nakamura, T.]]
+[[Category: Mukai Y]]
-[[Category: Tsutsumi, Y.]]
+[[Category: Nakamura T]]
-[[Category: Yamagata, Y.]]
+[[Category: Tsutsumi Y]]
-[[Category: Antagonistic activity]]
+[[Category: Yamagata Y]]
-[[Category: Cell membrane]]
-[[Category: Cytokine]]
-[[Category: Lipoprotein]]
-[[Category: Membrane]]
-[[Category: Myristate]]
-[[Category: Phage display system]]
-[[Category: Phosphoprotein]]
-[[Category: Secreted]]
-[[Category: Signal-anchor]]
-[[Category: Tnfr1 specific]]
-[[Category: Transmembrane]]
-[[Category: Trimer]]
-[[Category: Tumor necrosis factor]]

2zpx

From Proteopedia

Current revision

TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity; R1antTNF-T8

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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