4frs

From Proteopedia

(Difference between revisions)

Current revision

Structure of BACE in complex with (S)-4-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium

Structural highlights

4frs is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.^[1] ^[2]

Publication Abstract from PubMed

Inhibition of BACE1 to prevent brain Abeta peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Abeta levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Abeta40 levels when administered orally to rats.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Abeta Reduction.,Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ ACS Med Chem Lett. 2012 Nov 8;3(11):897-902. Epub 2012 Jul 12. PMID:23412139^[3]

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

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ. Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Abeta Reduction. ACS Med Chem Lett. 2012 Nov 8;3(11):897-902. Epub 2012 Jul 12. PMID:23412139 doi:10.1021/ml3001165

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4frs"

Categories: Homo sapiens | Large Structures | Orth P

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4frs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FRS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FRS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0V6:(2Z,6S)-6-{3-CHLORO-5-[5-(PROP-1-YN-1-YL)PYRIDIN-3-YL]THIOPHEN-2-YL}-2-IMINO-3,6-DIMETHYLTETRAHYDROPYRIMIDIN-4(1H)-ONE'>0V6</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0V6:(2Z,6S)-6-{3-CHLORO-5-[5-(PROP-1-YN-1-YL)PYRIDIN-3-YL]THIOPHEN-2-YL}-2-IMINO-3,6-DIMETHYLTETRAHYDROPYRIMIDIN-4(1H)-ONE'>0V6</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=4frs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4frs OCA], [https://pdbe.org/4frs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4frs RCSB], [https://www.ebi.ac.uk/pdbsum/4frs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4frs ProSAT]</span></td></tr>
 </table>

4frs

From Proteopedia

Current revision

Structure of BACE in complex with (S)-4-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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