5ujb

From Proteopedia

(Difference between revisions)

Current revision

Structure of a Mcl-1 Inhibitor Binding to Site 3 of Human Serum Albumin

Structural highlights

5ujb 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 2.7Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ALBU_HUMAN Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.^[1] ^[2] ^[3] ^[4]

Function

ALBU_HUMAN Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.^[5]

Publication Abstract from PubMed

Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.

Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin.,Zhao B, Sensintaffar J, Bian Z, Belmar J, Lee T, Olejniczak ET, Fesik SW Bioorg Med Chem. 2017 Mar 29. pii: S0968-0896(17)30251-1. doi:, 10.1016/j.bmc.2017.03.060. PMID:28428041^[6]

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

References

↑ Sunthornthepvarakul T, Angkeow P, Weiss RE, Hayashi Y, Refetoff S. An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families. Biochem Biophys Res Commun. 1994 Jul 29;202(2):781-7. PMID:8048949
↑ Rushbrook JI, Becker E, Schussler GC, Divino CM. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. 1995 Feb;80(2):461-7. PMID:7852505
↑ Wada N, Chiba H, Shimizu C, Kijima H, Kubo M, Koike T. A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred. J Clin Endocrinol Metab. 1997 Oct;82(10):3246-50. PMID:9329347
↑ Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, Angsusingha K, Kitvitayasak S, Scherberg NH, Refetoff S. Familial dysalbuminemic hypertriiodothyroninemia: a new, dominantly inherited albumin defect. J Clin Endocrinol Metab. 1998 May;83(5):1448-54. PMID:9589637
↑ Lu J, Stewart AJ, Sadler PJ, Pinheiro TJ, Blindauer CA. Albumin as a zinc carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans. 2008 Dec;36(Pt 6):1317-21. doi: 10.1042/BST0361317. PMID:19021548 doi:10.1042/BST0361317
↑ Zhao B, Sensintaffar J, Bian Z, Belmar J, Lee T, Olejniczak ET, Fesik SW. Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin. Bioorg Med Chem. 2017 Mar 29. pii: S0968-0896(17)30251-1. doi:, 10.1016/j.bmc.2017.03.060. PMID:28428041 doi:http://dx.doi.org/10.1016/j.bmc.2017.03.060

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/5ujb"

Categories: Homo sapiens | Large Structures | Zhao B

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5ujb is ON HOLD
+==Structure of a Mcl-1 Inhibitor Binding to Site 3 of Human Serum Albumin==
+<StructureSection load='5ujb' size='340' side='right'caption='[[5ujb]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ujb]] 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=5UJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UJB FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6AK:4-{8-CHLORO-11-[3-(4-CHLORO-3,5-DIMETHYLPHENOXY)PROPYL]-1-OXO-7-(1,3,5-TRIMETHYL-1H-PYRAZOL-4-YL)-4,5-DIHYDRO-1H-[1,4]DIAZEPINO[1,2-A]INDOL-2(3H)-YL}-1-METHYL-1H-INDOLE-6-CARBOXYLIC+ACID'>6AK</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=5ujb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ujb OCA], [https://pdbe.org/5ujb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ujb RCSB], [https://www.ebi.ac.uk/pdbsum/5ujb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ujb ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:[https://omim.org/entry/103600 103600]. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.<ref>PMID:8048949</ref> <ref>PMID:7852505</ref> <ref>PMID:9329347</ref> <ref>PMID:9589637</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.<ref>PMID:19021548</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.
-Authors: Zhao, B.
+Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin.,Zhao B, Sensintaffar J, Bian Z, Belmar J, Lee T, Olejniczak ET, Fesik SW Bioorg Med Chem. 2017 Mar 29. pii: S0968-0896(17)30251-1. doi:, 10.1016/j.bmc.2017.03.060. PMID:28428041<ref>PMID:28428041</ref>
-Description: Structure of a Mcl-1 Inhibitor Binding to Site 3 of Human Serum Albumin
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhao, B]]
+<div class="pdbe-citations 5ujb" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Albumin 3D structures|Albumin 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Zhao B]]

5ujb

From Proteopedia

Current revision

Structure of a Mcl-1 Inhibitor Binding to Site 3 of Human Serum Albumin

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox