7onr

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
==PARP1 catalytic domain in complex with 8-chloroquinazolinone-based inhibitor (compound 9)==
==PARP1 catalytic domain in complex with 8-chloroquinazolinone-based inhibitor (compound 9)==
-
<StructureSection load='7onr' size='340' side='right'caption='[[7onr]]' scene=''>
+
<StructureSection load='7onr' size='340' side='right'caption='[[7onr]], [[Resolution|resolution]] 2.05&Aring;' 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=7ONR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ONR FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[7onr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ONR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ONR 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=7onr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7onr OCA], [https://pdbe.org/7onr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7onr RCSB], [https://www.ebi.ac.uk/pdbsum/7onr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7onr 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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=VKW:8-chloranyl-2-[3-[4-(1,5-dimethylimidazol-2-yl)piperazin-1-yl]propyl]-3~{H}-quinazolin-4-one'>VKW</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=7onr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7onr OCA], [https://pdbe.org/7onr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7onr RCSB], [https://www.ebi.ac.uk/pdbsum/7onr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7onr ProSAT]</span></td></tr>
</table>
</table>
 +
== Function ==
 +
[[https://www.uniprot.org/uniprot/PARP1_HUMAN PARP1_HUMAN]] Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.<ref>PMID:17177976</ref> <ref>PMID:18172500</ref> <ref>PMID:19344625</ref> <ref>PMID:19661379</ref>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
 +
 +
Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-m ethylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.,Johannes JW, Balazs A, Barratt D, Bista M, Chuba MD, Cosulich S, Critchlow SE, Degorce SL, Di Fruscia P, Edmondson SD, Embrey K, Fawell S, Ghosh A, Gill SJ, Gunnarsson A, Hande SM, Heightman TD, Hemsley P, Illuzzi G, Lane J, Larner C, Leo E, Liu L, Madin A, Martin S, McWilliams L, O'Connor MJ, Orme JP, Pachl F, Packer MJ, Pei X, Pike A, Schimpl M, She H, Staniszewska AD, Talbot V, Underwood E, Varnes JG, Xue L, Yao T, Zhang K, Zhang AX, Zheng X J Med Chem. 2021 Sep 27. doi: 10.1021/acs.jmedchem.1c01012. PMID:34570508<ref>PMID:34570508</ref>
 +
 +
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 7onr" style="background-color:#fffaf0;"></div>
 +
== References ==
 +
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
-
[[Category: Balazs A]]
+
[[Category: Balazs, A]]
-
[[Category: Barratt D]]
+
[[Category: Barratt, D]]
-
[[Category: Bista M]]
+
[[Category: Bista, M]]
-
[[Category: Chuba M]]
+
[[Category: Chuba, M]]
-
[[Category: Degorce SL]]
+
[[Category: Degorce, S L]]
-
[[Category: Di Fruscia P]]
+
[[Category: Embrey, K]]
-
[[Category: Embrey K]]
+
[[Category: Fruscia, P Di]]
-
[[Category: Ghosh A]]
+
[[Category: Ghosh, A]]
-
[[Category: Gill S]]
+
[[Category: Gill, S]]
-
[[Category: Gunnarsson A]]
+
[[Category: Gunnarsson, A]]
-
[[Category: Hande S]]
+
[[Category: Hande, S]]
-
[[Category: Hemsley P]]
+
[[Category: Hemsley, P]]
-
[[Category: Illuzzi G]]
+
[[Category: Illuzzi, G]]
-
[[Category: Johannes JW]]
+
[[Category: Johannes, J W]]
-
[[Category: Lane J]]
+
[[Category: Lane, J]]
-
[[Category: Larner C]]
+
[[Category: Larner, C]]
-
[[Category: Leo E]]
+
[[Category: Leo, E]]
-
[[Category: Madin A]]
+
[[Category: Madin, A]]
-
[[Category: Martin S]]
+
[[Category: Martin, S]]
-
[[Category: McWilliams L]]
+
[[Category: McWilliams, L]]
-
[[Category: Orme J]]
+
[[Category: Orme, J]]
-
[[Category: Pachl F]]
+
[[Category: Pachl, F]]
-
[[Category: Packer M]]
+
[[Category: Packer, M]]
-
[[Category: Pike A]]
+
[[Category: Pike, A]]
-
[[Category: Schimpl M]]
+
[[Category: Schimpl, M]]
-
[[Category: Staniszewska AD]]
+
[[Category: Staniszewska, A D]]
-
[[Category: Talbot V]]
+
[[Category: Talbot, V]]
-
[[Category: Underwood E]]
+
[[Category: Underwood, E]]
-
[[Category: Varnes GJ]]
+
[[Category: Varnes, G J]]
-
[[Category: Zhang A]]
+
[[Category: Zhang, A]]
-
[[Category: Zheng X]]
+
[[Category: Zheng, X]]
 +
[[Category: Oncology]]
 +
[[Category: Parp inhibitor]]
 +
[[Category: Selectivity]]
 +
[[Category: Structure-based drug design]]
 +
[[Category: Synthetic lethal therapy]]
 +
[[Category: Transferase]]

Revision as of 05:56, 6 October 2021

PARP1 catalytic domain in complex with 8-chloroquinazolinone-based inhibitor (compound 9)

PDB ID 7onr

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7onr"
Personal tools