Small Molecule Inhibitors of Ca2+-S100B Reveal Two Protein Conformations

被引：14

作者：

Cavalier, Michael C. ^{[1
]}

Ansari, Mohd Imran ^{[3
]}

Pierce, Adam D. ^{[1
]}

Wilder, Paul T. ^{[1
,2
]}

McKnight, Laura E. ^{[1
]}

Raman, E. Prabhu ^{[3
]}

Neau, David B. ^{[5
]}

Bezawada, Padmavani ^{[3
]}

Alasady, Milad J. ^{[1
]}

Charpentier, Thomas H. ^{[1
]}

Varney, Kristen M. ^{[1
]}

Toth, Eric A. ^{[1
,2
,4
]}

MacKerell, Alexander D., Jr. ^{[2
,3
]}

Coop, Andrew ^{[2
,3
]}

Weber, David J. ^{[1
,2
]}

机构：

[1] Univ Maryland, Sch Med, CBT, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA

[3] Univ Maryland, Sch Pharm, Comp Aided Drug Design Ctr, Baltimore, MD 21201 USA

[4] Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA

[5] NE CAT, Argonne, IL 60439 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 02期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

GENERAL FORCE-FIELD; S100B-P53; INTERACTION; METASTATIC MELANOMA; SITE-IDENTIFICATION; MALIGNANT-MELANOMA; IN-VITRO; BINDING; PENTAMIDINE; SURVIVAL; SYSTEM;

D O I：

10.1021/acs.jmedchem.5b01369

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100Bp53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of (Ca)S100Binhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the FF-gate. For symmetric pentamidine analogues ((Ca)S100B5a, (Ca)S100B6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((Ca)S100B17), this same channel was open. The (Ca)S100B17 structure illustrates, for the first time, a pentamidine analog capable of binding the open form of the FF-gate and provides a means to block all three hot spots on (Ca)S100B, which will impact next generation (Ca)S100Bp53 inhibitor design.

引用

页码：592 / 608

页数：17

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