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| ==Structure== | | ==Structure== |
| ===General Structure===
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| There are two distinct classes of HMGRs, class I, which is only found in eukaryotes and are membrane bound and class II, which is found in prokaryotes and are soluble. <ref>PMID:11349148</ref> HMGR contains 8 transmembrane domains, which have yet to be successfully crystallized, that anchor the protein to the membrane of the endoplasmic reticulum. <ref name="Roitelman">PMID:1374417</ref> The catalytic portion of human HMGR forms a tetramer, with the individual monomers winding around each other. <ref name="Roitelman"/> Within the tetramer, the monomers are arranged into <scene name='HMG-CoA_Reductase/1dq8_2_dimers/1'>two dimers</scene>, each of which contains <scene name='HMG-CoA_Reductase/1dq8_2_active_sites/1'>two active sites </scene>which are formed by residues form both monomers. Each monomer contains <scene name='HMG-CoA_Reductase/1dq8_star3_domains/1'>three domains </scene>, the <scene name='HMG-CoA_Reductase/1dq8_n_domain/2'>N-domain</scene>, the <scene name='HMG-CoA_Reductase/1dq8_l_domain/1'>L-Domain</scene>, and the <scene name='HMG-CoA_Reductase/1dq8_s_domain/1'>S-Domain</scene>. The L-domain is unique to HMGRs while the S-domain, which forms the binding site for NADP, resembles that of [[ferredoxin]]. The S and L domains are connected by a <scene name='HMG-CoA_Reductase/1dq8_cis_loop/1'>“cis-loop”</scene> which is essential for the HMG-binding site. <ref name="Roitelman"/> Salt bridges between residues R641 and E782 as well as <scene name='HMG-CoA_Reductase/1dq8_cis_loop/2'>hydrogen bonds</scene> between E700 and E700 on neighboring monomers compliment the largely hydrophobic dimer-dimer interface. <ref name="Roitelman"/>
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| | | <applet load='1aoi' size='600' frame='true' align='right' caption='' /> |
| | | </td> |
| ===Substrate Binding & Catalytic Mechanism===
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| <applet load="1dqa2.pdb" size="400" color="white" frame="true" spin="on" Scene ="HMG-CoA_Reductase/1dqa_starting_2/1" caption="Crystal Structure of Human HMGR, [[1dqa]]" align="right"/> | | <div style="background-color: #ffe8e8;overflow: auto;height: 600px;width: 100%;"> |
| [[Image: Reactin_scheme.PNG|300px|left|thumb| Chemical Reaction Catalyzed by HMGR]]
| | {{:User:Eran Hodis/Sandbox8}} |
| The HMG-CoA and NADPH molecules make numerous contacts with the L and S domains in forming the four active sites. The CoA is located in a <scene name='HMG-CoA_Reductase/1dqa_nadp_and_coa/1'>positively charged pocket near the enzyme surface</scene>, with the pantothenic acid moiety extending into the interior of the protein. <scene name='HMG-CoA_Reductase/1dqa_tyr_491/2'>Tyrosine 479 forms a hydrophobic lid</scene> over the CoA adenine base, shielding the extended binding pocket from solution. The NADPH binding site is formed primarily by the S-domain with <scene name='HMG-CoA_Reductase/1dqa_loop/2'>a loop region</scene> playing a critical role in binding. <ref name="Roitelman"/>
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| The HMG binding pocket is the site of catalysis in HMGR. <scene name='HMG-CoA_Reductase/1dqa_cis_loop2/2'> The“cis-loop” that bends over the top of HMG </scene> is a critical structural element of this binding site. Residues <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> and are positioned in the active site as is <scene name='HMG-CoA_Reductase/1dqa_k691/2'>K691 which is only 2.7 angstroms from the HMG O2 carbonyl oxygen</scene>. It is this K691 that presumably stabilizes the negatively charged oxygen on the first mevaldyl-CoA intermediate. <ref name="Roitelman"/> The mevaldyl CoA intermediate is subsequently converted to Mavaldehyde with added stabilization from <scene name='HMG-CoA_Reductase/1dqa_h866/2'>H866, which is within hydrogen bonding distance of the thiol group</scene>. It is then believed that the close proximity of <scene name='HMG-CoA_Reductase/1dqa_e_and_d/2'>E559 and D767</scene> increases the pKA of E559, allowing it to be a proton donor for the reduction of mevaldehyde into mevalonate. <ref name="Roitelman"/>
| | </tr> |
| <br /> | | </table> |
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| ==Regulation of HMG-CoA Reductase== | | ==Regulation of HMG-CoA Reductase== |
