8svy

From Proteopedia

(Difference between revisions)

Current revision

MBP-Mcl1 in complex with ligand 10

Structural highlights

8svy is a 1 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.47Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MALE_ECO57 Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity).MCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.^[1]

Publication Abstract from PubMed

Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (R(a))-10 and (R(a))-15, possessing remarkable cellular potency and properties.

Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.,Demin S, Peschiulli A, Velter AI, Vos A, De Boeck B, Miller B, Rombouts FJR, Reuillon T, Lento W, Blanco MD, Jouffroy M, Steyvers H, Bekkers M, Altrocchi C, Pietrak B, Koo SJ, Szewczuk L, Attar R, Philippar U ACS Med Chem Lett. 2023 Jul 3;14(7):955-961. doi: 10.1021/acsmedchemlett.3c00141. , eCollection 2023 Jul 13. PMID:37465311^[2]

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

References

↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
↑ Demin S, Peschiulli A, Velter AI, Vos A, De Boeck B, Miller B, Rombouts FJR, Reuillon T, Lento W, Blanco MD, Jouffroy M, Steyvers H, Bekkers M, Altrocchi C, Pietrak B, Koo SJ, Szewczuk L, Attar R, Philippar U. Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1. ACS Med Chem Lett. 2023 Jul 3;14(7):955-961. PMID:37465311 doi:10.1021/acsmedchemlett.3c00141

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/8svy"

Categories: Escherichia coli | Homo sapiens | Large Structures | Miller BR | Shaffer P

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8svy is ON HOLD  until Paper Publication
+==MBP-Mcl1 in complex with ligand 10==
+<StructureSection load='8svy' size='340' side='right'caption='[[8svy]], [[Resolution|resolution]] 1.47&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8svy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SVY 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]] 1.47&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene>, <scene name='pdbligand=WUC:(15P)-17-chloro-33-fluoro-12-[(2-methoxyethoxy)methyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,13,14,22-pentaazaheptacyclo[27.7.1.1~4,7~.0~11,15~.0~16,21~.0~20,24~.0~30,35~]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic+acid'>WUC</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=8svy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8svy OCA], [https://pdbe.org/8svy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8svy RCSB], [https://www.ebi.ac.uk/pdbsum/8svy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8svy ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/MALE_ECO57 MALE_ECO57] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity).[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (R(a))-10 and (R(a))-15, possessing remarkable cellular potency and properties.
-Authors: Miller, B.R., Shaffer, P.
+Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.,Demin S, Peschiulli A, Velter AI, Vos A, De Boeck B, Miller B, Rombouts FJR, Reuillon T, Lento W, Blanco MD, Jouffroy M, Steyvers H, Bekkers M, Altrocchi C, Pietrak B, Koo SJ, Szewczuk L, Attar R, Philippar U ACS Med Chem Lett. 2023 Jul 3;14(7):955-961. doi: 10.1021/acsmedchemlett.3c00141. , eCollection 2023 Jul 13. PMID:37465311<ref>PMID:37465311</ref>
-Description: MBP-Mcl1 in complex with ligand 10
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Shaffer, P]]
+<div class="pdbe-citations 8svy" style="background-color:#fffaf0;"></div>
-[[Category: Miller, B.R]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Escherichia coli]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Miller BR]]
+[[Category: Shaffer P]]

8svy

From Proteopedia

Current revision

MBP-Mcl1 in complex with ligand 10

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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