View source for 7shi


==Crystal Structure of Cytochrome P450 AmphL from Streptomyces nodosus and the Structural Basis for Substrate Selectivity in Macrolide Metabolizing P450s==
<StructureSection load='7shi' size='340' side='right'caption='[[7shi]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SHI 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]] 2.0000277&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4UH:(1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,19E,22E,33S,35S,36R,37S)-33-[(3-amino-3,6-dideoxy-beta-D-mannopyranosyl)oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,22-diene-36-carboxylic+acid'>4UH</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7shi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7shi OCA], [https://pdbe.org/7shi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7shi RCSB], [https://www.ebi.ac.uk/pdbsum/7shi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7shi ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
AmphL is a cytochrome P450 enzyme that catalyzes the C8 oxidation of 8-deoxyamphotericin B to the polyene macrolide antibiotic, amphotericin B. To understand this substrate selectivity, we solved the crystal structure of AmphL to a resolution of 2.0A in complex with amphotericin B and performed molecular dynamics simulations. A detailed comparison with the closely related P450, PimD, which catalyzes the epoxidation of 4,5-desepoxypimaricin to the macrolide antibiotic, pimaricin, reveals key catalytic structural features responsible for stereo- and regio-selective oxidation. Both P450s have a similar access channel that runs parallel to the active site I helix over the surface of the heme. Molecular dynamics simulations of substrate binding reveal PimD can "pull" substrates further into the P450 access channel owing to additional electrostatic interactions between the protein and the carboxyl group attached to the hemiketal ring of 4,5-desepoxypimaricin. This substrate interaction is absent in AmphL although the additional substrate -OH groups in 8-deoxyamphotericin B help to correctly position the substrate for C8 oxidation. Simulations of the oxy-complex indicates that these -OH groups may also participate in a proton relay network required for O2 activation as has been suggested for two other macrolide P450s, PimD and P450eryF. These findings provide experimentally testable models that can potentially contribute to a new generation of novel macrolide antibiotics with enhanced antifungal and/or antiprotozoal efficacy.

Structural Analysis of P450 AmphL from S. nodosus Provides Insights into Substrate Selectivity of Polyene Macrolide Antibiotic Biosynthetic P450s.,Amaya JA, Lamb DC, Kelly SL, Caffrey P, Murarka VC, Poulos TL J Biol Chem. 2022 Feb 18:101746. doi: 10.1016/j.jbc.2022.101746. PMID:35189143<ref>PMID:35189143</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7shi" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Amaya JA]]
[[Category: Poulos TL]]