View source for 7cd0


==Crystal structure of the 2-iodoporphobilinogen-bound ES2 intermediate form of human hydroxymethylbilane synthase==
<StructureSection load='7cd0' size='340' side='right'caption='[[7cd0]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CD0 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]] 2.31&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7J8:3-[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-3-(3-hydroxy-3-oxopropyl)-5-methyl-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-1~{H}-pyrrol-3-yl]propanoic+acid'>7J8</scene>, <scene name='pdbligand=FWL:3-[5-(aminomethyl)-4-(carboxymethyl)-2-iodo-1H-pyrrol-3-yl]propanoic+acid'>FWL</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=7cd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cd0 OCA], [https://pdbe.org/7cd0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cd0 RCSB], [https://www.ebi.ac.uk/pdbsum/7cd0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cd0 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Hydroxymethylbilane synthase (HMBS), which is involved in the heme biosynthesis pathway, has a dipyrromethane cofactor and combines four porphobilinogen (PBG) molecules to form a linear tetrapyrrole, hydroxymethylbilane. Enzyme kinetic study of human HMBS using a PBG-derivative, 2-iodoporphobilinogen (2-I-PBG), exhibited noncompetitive inhibition with the inhibition constant being 5.4 +/- 0.3 microM. To elucidate the reaction mechanism of HMBS in detail, crystal structure analysis of 2-I-PBG-bound holo-HMBS and its reaction intermediate possessing two PBG molecules (ES2), and inhibitor-free ES2 was performed at 2.40, 2.31, and 1.79 A resolution, respectively. Their overall structures are similar to that of inhibitor-free holo-HMBS, and the differences are limited near the active site. In both 2-I-PBG-bound structures, 2-I-PBG is located near the terminus of the cofactor or the tetrapyrrole chain. The propionate group of 2-I-PBG interacts with the side chain of Arg173, and its acetate group is associated with the side chains of Arg26 and Ser28. Furthermore, the aminomethyl group and pyrrole nitrogen of 2-I-PBG form hydrogen bonds with the side chains of Gln34 and Asp99, respectively. These amino acid residues form a single substrate-binding site, where each of the four PBG molecules covalently binds to the cofactor (or oligopyrrole chain) consecutively, ultimately forming a hexapyrrole chain. Molecular dynamics simulation of the ES2 intermediate suggested that the thermal fluctuation of the lid and cofactor-binding loops causes substrate recruitment and oligopyrrole chain shift needed for consecutive condensation. Finally, the hexapyrrole chain is hydrolyzed self-catalytically to produce hydroxymethylbilane.

Crystal structures of hydroxymethylbilane synthase complexed with a substrate analog: a single substrate-binding site for four consecutive condensation steps.,Sato H, Sugishima M, Tsukaguchi M, Masuko T, Iijima M, Takano M, Omata Y, Hirabayashi K, Wada K, Hisaeda Y, Yamamoto K Biochem J. 2021 Mar 12;478(5):1023-1042. doi: 10.1042/BCJ20200996. PMID:33600566<ref>PMID:33600566</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7cd0" style="background-color:#fffaf0;"></div>

==See Also==
*[[Porphobilinogen Deaminase|Porphobilinogen Deaminase]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Hirabayashi K]]
[[Category: Sato H]]
[[Category: Sugishima M]]
[[Category: Tsukaguchi M]]
[[Category: Wada K]]