7jra

From Proteopedia

(Difference between revisions)

Revision as of 15:09, 18 October 2023

HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol

Structural highlights

7jra 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 2.1Å
Ligands:	,
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]

Publication Abstract from PubMed

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFalpha). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFalpha trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFalpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.,Xiao HY, Li N, Duan JJ, Jiang B, Lu Z, Ngu K, Tino J, Kopcho LM, Lu H, Chen J, Tebben AJ, Sheriff S, Chang CY, Yanchunas J Jr, Calambur D, Gao M, Shuster DJ, Susulic V, Xie JH, Guarino VR, Wu DR, Gregor KR, Goldstine CB, Hynes J Jr, Macor JE, Salter-Cid L, Burke JR, Shaw PJ, Dhar TGM J Med Chem. 2020 Dec 1. doi: 10.1021/acs.jmedchem.0c01732. PMID:33261314^[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
↑ Xiao HY, Li N, Duan JJ, Jiang B, Lu Z, Ngu K, Tino J, Kopcho LM, Lu H, Chen J, Tebben AJ, Sheriff S, Chang CY, Yanchunas J Jr, Calambur D, Gao M, Shuster DJ, Susulic V, Xie JH, Guarino VR, Wu DR, Gregor KR, Goldstine CB, Hynes J Jr, Macor JE, Salter-Cid L, Burke JR, Shaw PJ, Dhar TGM. Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFalpha Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches. J Med Chem. 2020 Dec 1. doi: 10.1021/acs.jmedchem.0c01732. PMID:33261314 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01732

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7jra"

Categories: Homo sapiens | Large Structures | Sheriff S

@@ Line 3: / Line 3: @@
 <StructureSection load='7jra' size='340' side='right'caption='[[7jra]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7jra]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JRA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JRA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7jra]] 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=7JRA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JRA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=VGY:2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol'>VGY</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TNF, TNFA, TNFSF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=VGY:2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol'>VGY</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jra OCA], [http://pdbe.org/7jra PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jra RCSB], [http://www.ebi.ac.uk/pdbsum/7jra PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jra ProSAT]</span></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=7jra FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jra OCA], [https://pdbe.org/7jra PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jra RCSB], [https://www.ebi.ac.uk/pdbsum/7jra PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jra ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[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).
+[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 ==
-[[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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Sheriff, S]]
+[[Category: Sheriff S]]
-[[Category: Asymmetric]]
-[[Category: Cytokine]]
-[[Category: Inhibitor]]
-[[Category: Lymphokine]]
-[[Category: Protein-protein interaction inhibitor]]
-[[Category: Tnf]]
-[[Category: Tumor necrosis factor alpha]]

7jra

From Proteopedia

Revision as of 15:09, 18 October 2023

HUMAN TNF-ALPHA IN COMPLEX WITH 2-[5-(3-chloro-4-{[(1R)-1-(2-fluorophenyl)ethyl]amino}quinolin-6-yl)pyrimidin-2-yl]propan-2-ol

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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