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| - | ===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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| - | ===Substrate Binding & Catalytic Mechanism===
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| - | [[Image: Reactin_scheme.PNG|300px|left|thumb| Chemical Reaction Catalyzed by HMGR]]
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| - | 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"/>
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Revision as of 02:26, 30 December 2010
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On October 7th, 2009 the Nobel Committee announced three structural biologists would share the 2009 Nobel Prize in Chemistry for studies of the the
ribosome. The ribosome is the machine in your cells that accurately and efficiently decodes the genetic information stored in your genome and synthesizes the corresponding polypeptide chain one amino acid at a time in the process of translation. Venkatraman Ramakrishnan of the M.R.C. Laboratory of Molecular Biology in Cambridge, England; Thomas A. Steitz of Yale University; and Ada E. Yonath of the Weizmann Institute of Science in Rehovot, Israel share the prize for the first atomic-resolution structures of the two subunits that come together to form an active ribosome. These structures are considered landmarks for the fact they showed clearly the major contributions to decoding and peptide bond synthesis come from RNA and not protein, as well as for the sheer size of the structures determined. These structures represent tour-de-force efforts in understanding fundamental processes in every organism on earth and will have direct impacts on how we fight pathogenic bacteria in the immediate future. Shown are both subunits of the ribosome, as well as that bind in the complex during the process of translation. (more...)
