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3q5h

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Revision as of 11:34, 17 July 2019

Clinically Useful Alkyl Amine Renin Inhibitors

Structural highlights

3q5h is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3gw5, 3km4, 3q3t, 3q4b
Gene:	REN, renin (HUMAN)
Activity:	Renin, with EC number 3.4.23.15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[RENI_HUMAN] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM: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).^[1] Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.^[2]

Function

[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.

Publication Abstract from PubMed

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.,Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA ACS Med Chem Lett. 2011 Aug 9;2(10):747-51. doi: 10.1021/ml200137x. eCollection, 2011 Oct 13. PMID:24900262^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
↑ Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet'al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. Epub 2009 Aug 6. PMID:19664745 doi:10.1016/j.ajhg.2009.07.010
↑ Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA. Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility. ACS Med Chem Lett. 2011 Aug 9;2(10):747-51. doi: 10.1021/ml200137x. eCollection, 2011 Oct 13. PMID:24900262 doi:http://dx.doi.org/10.1021/ml200137x

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3q5h"

@@ Line 1: / Line 1: @@
 ==Clinically Useful Alkyl Amine Renin Inhibitors==
-<StructureSection load='3q5h' size='340' side='right' caption='[[3q5h]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
+<StructureSection load='3q5h' size='340' side='right'caption='[[3q5h]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3q5h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3Q5H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3Q5H FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=RX6:METHYL+(2-{(R)-(3-CHLOROPHENYL)[(3R)-1-({(2S)-1-(METHYLAMINO)-3-[(3R)-TETRAHYDRO-2H-PYRAN-3-YL]PROPAN-2-YL}CARBAMOYL)PIPERIDIN-3-YL]METHOXY}ETHYL)CARBAMATE'>RX6</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RX6:METHYL+(2-{(R)-(3-CHLOROPHENYL)[(3R)-1-({(2S)-1-(METHYLAMINO)-3-[(3R)-TETRAHYDRO-2H-PYRAN-3-YL]PROPAN-2-YL}CARBAMOYL)PIPERIDIN-3-YL]METHOXY}ETHYL)CARBAMATE'>RX6</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3gw5|3gw5]], [[3km4|3km4]], [[3q3t|3q3t]], [[3q4b|3q4b]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">REN, renin ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
@@ Line 31: / Line 31: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Renin]]
 [[Category: McKeever, B M]]

3q5h

From Proteopedia

Revision as of 11:34, 17 July 2019

Clinically Useful Alkyl Amine Renin Inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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