4mro: Difference between revisions

Revision as of 10:03, 28 December 2022

Human GKRP bound to AMG-5980 and S6P

Structural highlights

4mro 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.
Ligands:	GOL, IOD, MG0, S6P, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GCKR_HUMAN Inhibits glucokinase by forming an inactive complex with this enzyme.

Publication Abstract from PubMed

In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.,St Jean DJ Jr, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Galbreath E, Helmering J, Hong FT, Jordan SR, Liu L, Kunz RK, Michelsen K, Nishimura N, Pennington LD, Poon SF, Reid D, Sivits G, Stec MM, Tadesse S, Tamayo N, Van G, Yang KC, Zhang J, Norman MH, Fotsch C, Lloyd DJ, Hale C J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747. Epub 2014 Jan 9. PMID:24405213^[1]

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

References

↑ St Jean DJ Jr, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Galbreath E, Helmering J, Hong FT, Jordan SR, Liu L, Kunz RK, Michelsen K, Nishimura N, Pennington LD, Poon SF, Reid D, Sivits G, Stec MM, Tadesse S, Tamayo N, Van G, Yang KC, Zhang J, Norman MH, Fotsch C, Lloyd DJ, Hale C. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles. J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747. Epub 2014 Jan 9. PMID:24405213 doi:https://dx.doi.org/10.1021/jm4016747

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] St Jean DJ Jr, Ashton KS, Bartberger MD, Chen J, Chmait S, Cupples R, Galbreath E, Helmering J, Hong FT, Jordan SR, Liu L, Kunz RK, Michelsen K, Nishimura N, Pennington LD, Poon SF, Reid D, Sivits G, Stec MM, Tadesse S, Tamayo N, Van G, Yang KC, Zhang J, Norman MH, Fotsch C, Lloyd DJ, Hale C. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles. J Med Chem. 2014 Jan 23;57(2):325-38. doi: 10.1021/jm4016747. Epub 2014 Jan 9. PMID:24405213 doi:https://dx.doi.org/10.1021/jm4016747

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='4mro' size='340' side='right'caption='[[4mro]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4mro]] 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=4MRO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MRO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4mro]] 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=4MRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MRO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MG0:2-(4-{4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]PIPERAZIN-1-YL}PHENYL)-1,1,1,3,3,3-HEXAFLUOROPROPAN-2-OL'>MG0</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MG0:2-(4-{4-[(6-AMINOPYRIDIN-3-YL)SULFONYL]PIPERAZIN-1-YL}PHENYL)-1,1,1,3,3,3-HEXAFLUOROPROPAN-2-OL'>MG0</scene>, <scene name='pdbligand=S6P:D-SORBITOL-6-PHOSPHATE'>S6P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mqu|4mqu]]</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=4mro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mro OCA], [https://pdbe.org/4mro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mro RCSB], [https://www.ebi.ac.uk/pdbsum/4mro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mro ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCKR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4mro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mro OCA], [http://pdbe.org/4mro PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mro RCSB], [http://www.ebi.ac.uk/pdbsum/4mro PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mro ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GCKR_HUMAN GCKR_HUMAN]] Inhibits glucokinase by forming an inactive complex with this enzyme.
+[https://www.uniprot.org/uniprot/GCKR_HUMAN GCKR_HUMAN] Inhibits glucokinase by forming an inactive complex with this enzyme.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ashton, K S]]
+[[Category: Ashton KS]]
-[[Category: Bartberger, M D]]
+[[Category: Bartberger MD]]
-[[Category: Chen, J]]
+[[Category: Chen J]]
-[[Category: Chmait, S]]
+[[Category: Chmait S]]
-[[Category: Cupples, R]]
+[[Category: Cupples R]]
-[[Category: Fotsch, C]]
+[[Category: Fotsch C]]
-[[Category: Galbreath, E]]
+[[Category: Galbreath E]]
-[[Category: Hale, C]]
+[[Category: Hale C]]
-[[Category: Helmering, J]]
+[[Category: Helmering J]]
-[[Category: Jean, D J.St]]
+[[Category: Jordan SR]]
-[[Category: Jordan, S R]]
+[[Category: Kunz K]]
-[[Category: Kunz, K]]
+[[Category: LLoyd DJ]]
-[[Category: LLoyd, D J]]
+[[Category: Liu L]]
-[[Category: Liu, L]]
+[[Category: Michelsen K]]
-[[Category: Michelsen, K]]
+[[Category: Nishimura N]]
-[[Category: Nishimura, N]]
+[[Category: Norman MH]]
-[[Category: Norman, M H]]
+[[Category: Pennington LD]]
-[[Category: Pennington, L D]]
+[[Category: Poon SF]]
-[[Category: Poon, S F]]
+[[Category: Sivits G]]
-[[Category: Sivits, G]]
+[[Category: St Jean DJ]]
-[[Category: Stec, M M]]
+[[Category: Stec MM]]
-[[Category: Tamayo, N]]
+[[Category: Tamayo N]]
-[[Category: Van, G]]
+[[Category: Van G]]
-[[Category: Yang, K]]
+[[Category: Yang K]]
-[[Category: Glucokinase]]
-[[Category: Phospho-fructose]]
-[[Category: Regulatory protein]]
-[[Category: Sis domain]]
-[[Category: Transferase inhibitor]]

4mro: Difference between revisions

Revision as of 10:03, 28 December 2022

Human GKRP bound to AMG-5980 and S6P

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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