5g1a: Difference between revisions
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==Bordetella Alcaligenes HDAH bound to PFSAHA== | |||
<StructureSection load='5g1a' size='340' side='right'caption='[[5g1a]], [[Resolution|resolution]] 1.42Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5g1a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Alcaligenes Alcaligenes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G1A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G1A 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]] 1.42Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=7H1:2,2,3,3,4,4,5,5,6,6,7,7-DODECAKIS(FLUORANYL)-~{N}-OXIDANYL-~{N}-PHENYL-OCTANEDIAMIDE'>7H1</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5g1a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g1a OCA], [https://pdbe.org/5g1a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g1a RCSB], [https://www.ebi.ac.uk/pdbsum/5g1a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g1a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HDAH_ALCSD HDAH_ALCSD] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: The analysis of the thermodynamic driving forces of ligand-protein binding has been suggested to be a key component for the selection and optimization of active compounds into drug candidates. The binding enthalpy as deduced from isothermal titration calorimetry (ITC) is usually interpreted assuming single-step binding of a ligand to one conformation of the target protein. Although successful in many cases, these assumptions are oversimplified approximations of the reality with flexible proteins and complicated binding mechanism in many if not most cases. The relationship between protein flexibility and thermodynamic signature of ligand binding is largely understudied. METHODS: Directed mutagenesis, X-ray crystallography, enzyme kinetics and ITC methods were combined to dissect the influence of loop flexibility on the thermodynamics and mechanism of ligand binding to histone deacetylase (HDAC)-like amidohydrolases. RESULTS: The general ligand-protein binding mechanism comprises an energetically demanding gate opening step followed by physical binding. Increased flexibility of the L2-loop in HDAC-like amidohydrolases facilitates access of ligands to the binding pocket resulting in predominantly enthalpy-driven complex formation. CONCLUSIONS: The study provides evidence for the great importance of flexibility adjacent to the active site channel for the mechanism and observed thermodynamic driving forces of molecular recognition in HDAC like enzymes. GENERAL SIGNIFICANCE: The flexibility or malleability in regions adjacent to binding pockets should be given more attention when designing better drug candidates. The presented case study also suggests that the observed binding enthalpy of protein-ligand systems should be interpreted with caution, since more complicated binding mechanisms may obscure the significance regarding potential drug likeness. | |||
The thermodynamic signature of ligand binding to histone deacetylase-like amidohydrolases is most sensitive to the flexibility in the L2-loop lining the active site pocket.,Meyners C, Kramer A, Yildiz O, Meyer-Almes FJ Biochim Biophys Acta. 2017 Apr 4. pii: S0304-4165(17)30126-5. doi:, 10.1016/j.bbagen.2017.04.001. PMID:28389333<ref>PMID:28389333</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5g1a" style="background-color:#fffaf0;"></div> | ||
[[Category: Meyer-Almes | |||
[[Category: | ==See Also== | ||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Alcaligenes]] | |||
[[Category: Large Structures]] | |||
[[Category: Kraemer A]] | |||
[[Category: Meyer-Almes FJ]] | |||
[[Category: Yildiz O]] | |||
Latest revision as of 16:35, 26 July 2023
Bordetella Alcaligenes HDAH bound to PFSAHABordetella Alcaligenes HDAH bound to PFSAHA
Structural highlights
FunctionPublication Abstract from PubMedBACKGROUND: The analysis of the thermodynamic driving forces of ligand-protein binding has been suggested to be a key component for the selection and optimization of active compounds into drug candidates. The binding enthalpy as deduced from isothermal titration calorimetry (ITC) is usually interpreted assuming single-step binding of a ligand to one conformation of the target protein. Although successful in many cases, these assumptions are oversimplified approximations of the reality with flexible proteins and complicated binding mechanism in many if not most cases. The relationship between protein flexibility and thermodynamic signature of ligand binding is largely understudied. METHODS: Directed mutagenesis, X-ray crystallography, enzyme kinetics and ITC methods were combined to dissect the influence of loop flexibility on the thermodynamics and mechanism of ligand binding to histone deacetylase (HDAC)-like amidohydrolases. RESULTS: The general ligand-protein binding mechanism comprises an energetically demanding gate opening step followed by physical binding. Increased flexibility of the L2-loop in HDAC-like amidohydrolases facilitates access of ligands to the binding pocket resulting in predominantly enthalpy-driven complex formation. CONCLUSIONS: The study provides evidence for the great importance of flexibility adjacent to the active site channel for the mechanism and observed thermodynamic driving forces of molecular recognition in HDAC like enzymes. GENERAL SIGNIFICANCE: The flexibility or malleability in regions adjacent to binding pockets should be given more attention when designing better drug candidates. The presented case study also suggests that the observed binding enthalpy of protein-ligand systems should be interpreted with caution, since more complicated binding mechanisms may obscure the significance regarding potential drug likeness. The thermodynamic signature of ligand binding to histone deacetylase-like amidohydrolases is most sensitive to the flexibility in the L2-loop lining the active site pocket.,Meyners C, Kramer A, Yildiz O, Meyer-Almes FJ Biochim Biophys Acta. 2017 Apr 4. pii: S0304-4165(17)30126-5. doi:, 10.1016/j.bbagen.2017.04.001. PMID:28389333[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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