8tjc

From Proteopedia

(Difference between revisions)

Current revision

Structure of human beta 1,3-N-acetylglucosaminyltransferase 2 with compound 8a

Structural highlights

8tjc is a 4 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 2.2Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

B3GN2_HUMAN Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine. Catalyzes the initiation and elongation of poly-N-acetyllactosamine chains. Shows a marked preference for Gal(beta1-4)Glc(NAc)-based acceptors (PubMed:9892646). Probably constitutes the main polylactosamine synthase.^[1] ^[2] ^[3]

Publication Abstract from PubMed

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

Imidazolone as an Amide Bioisostere in the Development of beta-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors.,Jackson JJ, Siegmund AC, Bai WJ, Reed AB, Birkholz AB, Campuzano IDG, Crequer-Grandhomme A, Hu R, Modak RV, Sudom A, Javier N, Sanders C, Lo MC, Xie F, Cee VJ, Manzanillo P, Allen JG J Med Chem. 2023 Dec 14;66(23):16120-16140. doi: 10.1021/acs.jmedchem.3c01517. , Epub 2023 Nov 21. PMID:37988652^[4]

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

References

↑ Shiraishi N, Natsume A, Togayachi A, Endo T, Akashima T, Yamada Y, Imai N, Nakagawa S, Koizumi S, Sekine S, Narimatsu H, Sasaki K. Identification and characterization of three novel beta 1,3-N-acetylglucosaminyltransferases structurally related to the beta 1,3-galactosyltransferase family. J Biol Chem. 2001 Feb 2;276(5):3498-507. doi: 10.1074/jbc.M004800200. Epub 2000, Oct 19. PMID:11042166 doi:http://dx.doi.org/10.1074/jbc.M004800200
↑ Praissman JL, Live DH, Wang S, Ramiah A, Chinoy ZS, Boons GJ, Moremen KW, Wells L. B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of alpha-dystroglycan. Elife. 2014 Oct 3;3. doi: 10.7554/eLife.03943. PMID:25279697 doi:http://dx.doi.org/10.7554/eLife.03943
↑ Zhou D, Dinter A, Gutierrez Gallego R, Kamerling JP, Vliegenthart JF, Berger EG, Hennet T. A beta-1,3-N-acetylglucosaminyltransferase with poly-N-acetyllactosamine synthase activity is structurally related to beta-1,3-galactosyltransferases. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):406-11. doi: 10.1073/pnas.96.2.406. PMID:9892646 doi:http://dx.doi.org/10.1073/pnas.96.2.406
↑ Jackson JJ, Siegmund AC, Bai WJ, Reed AB, Birkholz AB, Campuzano IDG, Créquer-Grandhomme A, Hu R, Modak RV, Sudom A, Javier N, Sanders C, Lo MC, Xie F, Cee VJ, Manzanillo P, Allen JG. Imidazolone as an Amide Bioisostere in the Development of β-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors. J Med Chem. 2023 Nov 21. PMID:37988652 doi:10.1021/acs.jmedchem.3c01517

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8tjc"

Categories: Homo sapiens | Large Structures | Min X | Sudom A

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8tjc is ON HOLD  until Paper Publication
+==Structure of human beta 1,3-N-acetylglucosaminyltransferase 2 with compound 8a==
+<StructureSection load='8tjc' size='340' side='right'caption='[[8tjc]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8tjc]] is a 4 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=8TJC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TJC 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=HI8:3-[(2~{R})-3,3-dimethylbutan-2-yl]-5-[(5~{S})-5-methyl-4-oxidanylidene-5-phenyl-1~{H}-imidazol-2-yl]-1~{H}-benzimidazol-2-one'>HI8</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=8tjc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tjc OCA], [https://pdbe.org/8tjc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tjc RCSB], [https://www.ebi.ac.uk/pdbsum/8tjc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tjc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/B3GN2_HUMAN B3GN2_HUMAN] Beta-1,3-N-acetylglucosaminyltransferase involved in the synthesis of poly-N-acetyllactosamine. Catalyzes the initiation and elongation of poly-N-acetyllactosamine chains. Shows a marked preference for Gal(beta1-4)Glc(NAc)-based acceptors (PubMed:9892646). Probably constitutes the main polylactosamine synthase.<ref>PMID:11042166</ref> <ref>PMID:25279697</ref> <ref>PMID:9892646</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.
-Authors:
+Imidazolone as an Amide Bioisostere in the Development of beta-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors.,Jackson JJ, Siegmund AC, Bai WJ, Reed AB, Birkholz AB, Campuzano IDG, Crequer-Grandhomme A, Hu R, Modak RV, Sudom A, Javier N, Sanders C, Lo MC, Xie F, Cee VJ, Manzanillo P, Allen JG J Med Chem. 2023 Dec 14;66(23):16120-16140. doi: 10.1021/acs.jmedchem.3c01517. , Epub 2023 Nov 21. PMID:37988652<ref>PMID:37988652</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8tjc" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Min X]]
+[[Category: Sudom A]]

8tjc

From Proteopedia

Current revision

Structure of human beta 1,3-N-acetylglucosaminyltransferase 2 with compound 8a

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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