4zpg

From Proteopedia

(Difference between revisions)

Current revision

BACE1 in complex with 8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one

Structural highlights

4zpg is a 1 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 2Å
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

The IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.,Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL Bioorg Med Chem Lett. 2015 Jun 29. pii: S0960-894X(15)00687-3. doi:, 10.1016/j.bmcl.2015.06.082. PMID:26195137^[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
↑ Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL. Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorg Med Chem Lett. 2015 Jun 29. pii: S0960-894X(15)00687-3. doi:, 10.1016/j.bmcl.2015.06.082. PMID:26195137 doi:http://dx.doi.org/10.1016/j.bmcl.2015.06.082

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/4zpg"

Categories: Homo sapiens | Large Structures | Orth P

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4zpg]] is a 1 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=4ZPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZPG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4QF:(5R,7S)-8-BENZYL-4-(CYCLOHEXYLAMINO)-1-(3-FLUOROPHENYL)-7-METHYL-1,3,8-TRIAZASPIRO[4.5]DEC-3-EN-2-ONE'>4QF</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]] 2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4QF:(5R,7S)-8-BENZYL-4-(CYCLOHEXYLAMINO)-1-(3-FLUOROPHENYL)-7-METHYL-1,3,8-TRIAZASPIRO[4.5]DEC-3-EN-2-ONE'>4QF</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=4zpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zpg OCA], [https://pdbe.org/4zpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zpg RCSB], [https://www.ebi.ac.uk/pdbsum/4zpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zpg ProSAT]</span></td></tr>
 </table>

4zpg

From Proteopedia

Current revision

BACE1 in complex with 8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox