Novel protein-inhibitor interactions in site 3 of Ca2+-bound S100B as discovered by X-ray crystallography

被引：8
|
作者：
Cavalier, Michael C. [1 ]
Melville, Zephan [1 ]
Aligholizadeh, Ehson [1 ]
Raman, E. Prabhu [2 ]
Yu, Wenbo [2 ]
Fang, Lei [2 ]
Alasady, Milad [1 ]
Pierce, Adam D. [1 ,3 ]
Wilder, Paul T. [1 ,3 ]
MacKerell, Alexander D., Jr. [2 ,3 ]
Weber, David J. [1 ,3 ]
机构：
[1] Univ Maryland, Sch Med, CBT, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Pharm, Comp Aided Drug Design Ctr, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
来源：
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY | 2016年 / 72卷
基金：
美国国家卫生研究院;
关键词：
S100B; inhibitor; melanoma; X-ray crystallography; drug design; COMPETITIVE SATURATION SILCS; SMALL-MOLECULE INHIBITORS; GENERAL FORCE-FIELD; MALIGNANT-MELANOMA; IDENTIFICATION; SYSTEM; CANCER; APOMORPHINE; PENTAMIDINE; AUTOMATION;
D O I：
10.1107/S2059798316005532
中图分类号：
Q5 [生物化学];
学科分类号：
071010 ; 081704 ;
摘要：
Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wildtype p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B-SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein-inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B.
引用
收藏
页码：753 / 760
页数：8
相关论文
共 28 条
  • [21] NOVEL NON-PRODUCTIVELY BOUND RIBONUCLEASE INHIBITOR COMPLEXES - HIGH-RESOLUTION X-RAY REFINEMENT STUDIES ON THE BINDING OF RNASE-A TO CYTIDYLYL-2',5'-GUANOSINE (2',5'CPG) AND DEOXYCYTIDYLYL-3',5'-GUANOSINE (3',5'DCPDG)
    AGUILAR, CF
    THOMAS, PJ
    MOSS, DS
    MILLS, A
    PALMER, RA
    BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1118 (01) : 6 - 20
  • [22] Complex interplay of hydrogen bonding, halogen bonding and π-interactions in methyl 2-(7-chloro-1H-pyrazolo[3,4-b]quinolin-1-yl) acetate: Synthesis, X-ray crystallography, energetic features and anti-urease efficacy
    Munir, Rubina
    Zaib, Sumera
    Khan, Imtiaz
    Islam, Zirwa Tul
    Gomila, Rosa M.
    McAdam, Christopher John
    Yeow, Colleen Hui Shiuan
    White, Jonathan M.
    Hokelek, Tuncer
    Al-Askar, Abdulaziz A.
    Elkaeed, Eslam B.
    Frontera, Antonio
    JOURNAL OF MOLECULAR STRUCTURE, 2023, 1287
  • [23] Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design
    Wyatt, Paul G.
    Woodhead, Andrew J.
    Berdini, Valerio
    Boulstridge, John A.
    Carr, Maria G.
    Cross, David M.
    Davis, Deborah J.
    Devine, Lindsay A.
    Early, Theresa R.
    Feltell, Ruth E.
    Lewis, E. Jonathan
    McMenamin, Rachel L.
    Navarro, Eva F.
    O'Brien, Michael A.
    O'Reilly, Marc
    Reule, Matthias
    Saxty, Gordon
    Seavers, Lisa C. A.
    Smith, Donna-Michelle
    Squires, Matt S.
    Trewartha, Gary
    Walker, Margaret T.
    Woolford, Alison J. -A.
    JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (16) : 4986 - 4999
  • [24] THE PREPARATION, X-RAY CRYSTAL-STRUCTURE AND THEORETICAL-STUDY OF [COCP2][S3N3], (CP = CYCLOPENTADIENYL), A NOVEL STACKING COMPOUND INCORPORATING MULTIPLE C-H...N(P-PI) INTERACTIONS
    JAGG, PN
    KELLY, PF
    RZEPA, HS
    WILLIAMS, DJ
    WOOLLINS, JD
    WYLIE, W
    JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1991, (14) : 942 - 944
  • [25] Synthesis, X-ray structures and NIR chiroptical properties of a series of dinuclear lanthanide(III) complexes [Ln2{μ-(S- or RS-pba)}4(HBpz3)2];: novel configurational chirality due to non-bonding Ln•••O interactions
    Subhan, MA
    Suzuki, T
    Fuyuhiro, A
    Kaizaki, S
    DALTON TRANSACTIONS, 2003, (19) : 3785 - 3791
  • [26] Synthesis, X-ray structures and NIR chiroptical properties of a series of dinuclear lanthanide(III) complexes [Ln2{μ-(S- or RS-pba)}4(HBpz3)2]; novel configurational chirality due to non-bonding Ln O interactions
    Subhan, Md. Abdus
    Suzuki, Takayoshi
    Fuyuhiro, Akira
    Kaizaki, Sumio
    Journal of the Chemical Society. Dalton Transactions, 2003, (19): : 3785 - 3791
  • [27] Synthesis, X-Ray Crystal Structure, Hirshfeld Surface Analysis, and Molecular Docking Study of Novel Hepatitis B (HBV) Inhibitor: 8-Fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one
    Ivashchenko, Aleksandr, V
    Mitkin, Oleg D.
    Kravchenko, Dmitry, V
    Kuznetsova, Irina, V
    Kovalenko, Sergiy M.
    Bunyatyan, Natalya D.
    Langer, Thierry
    CRYSTALS, 2019, 9 (08):
  • [28] CONFORMATIONAL STUDY OF A POTENT HUMAN RENIN INHIBITOR - X-RAY CRYSTAL-STRUCTURE OF ISOPROPYL (2R,3S)-4-CYCLOHEXYL-2-HYDROXY-3-(N-[(2R)-2-MORPHOLINOCARBONYLMETHYL-3-(1-NAPHTHYL)PROPIONYL]-L-HISTIDYLAMINO)BUTYRATE (KRI-1314), A PENTAPEPTIDE ANALOG WITH AMINO-ACID-SEQUENCE CORRESPONDING TO THE CLEAVAGE SITE OF ANGIOTENSINOGEN
    DOI, M
    IN, Y
    INOUE, M
    ISHIDA, T
    IIZUKA, K
    AKAHANE, K
    HARADA, H
    UMEYAMA, H
    KISO, Y
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1991, (05): : 1153 - 1158
123