3own
From Proteopedia
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| - | + | ==Potent macrocyclic renin inhibitors== | |
| - | === | + | <StructureSection load='3own' size='340' side='right' caption='[[3own]], [[Resolution|resolution]] 2.00Å' scene=''> |
| - | + | == Structural highlights == | |
| + | <table><tr><td colspan='2'>[[3own]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OWN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OWN FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3OW:(2S,4S)-4-HYDROXY-2-(1-METHYLETHYL)-4-[(4S,13S)-18-[METHYL(METHYLSULFONYL)AMINO]-2,15-DIOXO-4-PHENYL-11-OXA-3,14-DIAZATRICYCLO[14.3.1.1~5,9~]HENICOSA-1(20),5(21),6,8,16,18-HEXAEN-13-YL]-N-(2-METHYLPROPYL)BUTANAMIDE'>3OW</scene>, <scene name='pdbligand=3OX:(2S,4S)-4-HYDROXY-2-(1-METHYLETHYL)-4-[(4R,13S)-18-[METHYL(METHYLSULFONYL)AMINO]-2,15-DIOXO-4-PHENYL-11-OXA-3,14-DIAZATRICYCLO[14.3.1.1~5,9~]HENICOSA-1(20),5(21),6,8,16,18-HEXAEN-13-YL]-N-(2-METHYLPROPYL)BUTANAMIDE'>3OX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3own FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3own OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3own RCSB], [http://www.ebi.ac.uk/pdbsum/3own PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[http://omim.org/entry/267430 267430]]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[http://omim.org/entry/613092 613092]]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the K(i) and the human plasma renin activity (HPRA)IC(50) was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (K(i)=3.3nM and HPRA IC(50)=7nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (K(i)=34nM and HPRA IC(50)=56nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin. | ||
| - | + | Design and synthesis of potent macrocyclic renin inhibitors.,Sund C, Belda O, Wiktelius D, Sahlberg C, Vrang L, Sedig S, Hamelink E, Henderson I, Agback T, Jansson K, Borkakoti N, Derbyshire D, Eneroth A, Samuelsson B Bioorg Med Chem Lett. 2010 Nov 5. PMID:21112780<ref>PMID:21112780</ref> | |
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| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
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==See Also== | ==See Also== | ||
*[[Renin|Renin]] | *[[Renin|Renin]] | ||
| - | + | == References == | |
| - | == | + | <references/> |
| - | + | __TOC__ | |
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Renin]] | [[Category: Renin]] | ||
| - | [[Category: Borkakoti, N | + | [[Category: Borkakoti, N]] |
| - | [[Category: Derbyshire, D | + | [[Category: Derbyshire, D]] |
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Protease]] | [[Category: Protease]] | ||
| - | [[Category: Renin]] | ||
Revision as of 06:56, 19 December 2014
Potent macrocyclic renin inhibitors
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