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6dm8

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==Understanding the Species Selectivity of Myeloid cell leukemia-1 (Mcl-1) inhibitors==
==Understanding the Species Selectivity of Myeloid cell leukemia-1 (Mcl-1) inhibitors==
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<StructureSection load='6dm8' size='340' side='right' caption='[[6dm8]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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<StructureSection load='6dm8' size='340' side='right'caption='[[6dm8]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6dm8]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DM8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6dm8]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DM8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6AK:4-{8-CHLORO-11-[3-(4-CHLORO-3,5-DIMETHYLPHENOXY)PROPYL]-1-OXO-7-(1,3,5-TRIMETHYL-1H-PYRAZOL-4-YL)-4,5-DIHYDRO-1H-[1,4]DIAZEPINO[1,2-A]INDOL-2(3H)-YL}-1-METHYL-1H-INDOLE-6-CARBOXYLIC+ACID'>6AK</scene>, <scene name='pdbligand=MAL:MALTOSE'>MAL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dm8 OCA], [http://pdbe.org/6dm8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dm8 RCSB], [http://www.ebi.ac.uk/pdbsum/6dm8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dm8 ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6AK:4-{8-CHLORO-11-[3-(4-CHLORO-3,5-DIMETHYLPHENOXY)PROPYL]-1-OXO-7-(1,3,5-TRIMETHYL-1H-PYRAZOL-4-YL)-4,5-DIHYDRO-1H-[1,4]DIAZEPINO[1,2-A]INDOL-2(3H)-YL}-1-METHYL-1H-INDOLE-6-CARBOXYLIC+ACID'>6AK</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dm8 OCA], [https://pdbe.org/6dm8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dm8 RCSB], [https://www.ebi.ac.uk/pdbsum/6dm8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dm8 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI]] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.
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[https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[https://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE] 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.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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To test for on target toxicity of a new chemical entity, it is important to have comparable binding affinities of the compound in the target proteins from humans and the test species. To evaluate our myeloid cell leukemia-1 (Mcl-1) inhibitors, we tested them against rodent Mcl-1 and found a significant loss of binding affinity when compared to that seen with human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences. One difference is human L246 (F226 in rat, F227 in mouse) in the ligand binding pocket. Mutating rat F226 to a Leu restores affinity, but the mouse F227L mutant still has a ligand affinity that is lower than that of human Mcl-1. Another mutation of mouse F267, located approximately 12 A from the ligand pocket, to the human/rat cysteine, F267C, improved the affinity and combined with F227L resulted in a mutant mouse protein with a binding affinity similar to that of human Mcl-1. To help understand the structural components of the affinity loss, we obtained an X-ray structure of a mouse Mcl-1/inhibitor complex and identified how the residue changes reduced compound complementarity. Finally, we tested Mcl-1 of other preclinical animal models (canine, monkey, rabbit, and ferret) that are identical to humans in terms of these two residues and found that their Mcl-1 bound our compounds with affinities comparable to that of human Mcl-1. These results have implications for understanding ligand selectivity for similar proteins and for the interpretation of preclinical toxicology studies with Mcl-1 inhibitors.
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Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors.,Zhao B, Arnold AL, Coronel MA, Lee JH, Lee T, Olejniczak ET, Fesik SW Biochemistry. 2018 Jul 31. doi: 10.1021/acs.biochem.8b00626. PMID:30011190<ref>PMID:30011190</ref>
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==See Also==
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*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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*[[Maltose-binding protein 3D structures|Maltose-binding protein 3D structures]]
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</div>
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<div class="pdbe-citations 6dm8" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Zhao, B]]
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[[Category: Escherichia coli K-12]]
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[[Category: Apoptosis]]
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[[Category: Large Structures]]
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[[Category: Cancer]]
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[[Category: Mus musculus]]
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[[Category: Drug discovery]]
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[[Category: Zhao B]]
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[[Category: Mcl-1]]
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[[Category: Signaling protein]]
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[[Category: Signaling protein-inhibitor complex]]
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Current revision

Understanding the Species Selectivity of Myeloid cell leukemia-1 (Mcl-1) inhibitors

PDB ID 6dm8

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