2X7T

Structures of human carbonic anhydrase II inhibitor complexes reveal a second binding site for steroidal and non-steroidal inhibitors.

2X7T の概要

• エントリーDOI: 10.2210/pdb2x7t/pdb
• 関連するPDBエントリー: 12CA 1A42 1AM6 1AVN 1BCD 1BIC 1BN1 1BN3 1BN4 1BNM 1BNN 1BNQ 1BNT 1BNU 1BNV 1BNW 1BV3 1CA2 1CA3 1CAH 1CAI 1CAJ 1CAK 1CAL 1CAM 1CAN 1CAO 1CAY 1CAZ 1CCS 1CCT 1CCU 1CIL 1CIM 1CIN 1CNB 1CNC 1CNG 1CNH 1CNI 1CNJ 1CNK 1CNW 1CNX 1CNY 1CRA 1CVA 1CVB 1CVC 1CVD 1CVE 1CVF 1CVH 1DCA 1DCB 1EOU 1F2W 1FQL 1FQM 1FQN 1FQR 1FR4 1FR7 1FSN 1FSQ 1FSR 1G0E 1G0F 1G1D 1G3Z 1G45 1G46 1G48 1G4J 1G4O 1G52 1G53 1G54 1H4N 1H9N 1H9Q 1HCA 1HEA 1HEB 1HEC 1HED 1HVA 1I8Z 1I90 1I91 1I9L 1I9M 1I9N 1I9O 1I9P 1I9Q 1IF4 1IF5 1IF6 1IF7 1IF8 1IF9 1KWQ 1KWR 1LG5 1LG6 1LGD 1LUG 1LZV 1MOO 1MUA 1OKL 1OKM 1OKN 1OQ5 1RAY 1RAZ 1RZA 1RZB 1RZC 1RZD 1RZE 1T9N 1TB0 1TBT 1TE3 1TEQ 1TEU 1TG3 1TG9 1TH9 1THK 1TTM 1UGA 1UGB 1UGC 1UGD 1UGE 1UGF 1UGG 1XEG 1XEV 1YDA 1YDB 1YDC 1YDD 1YO0 1YO1 1YO2 1Z9Y 1ZE8 1ZFK 1ZFQ 1ZGE 1ZGF 1ZH9 1ZSA 1ZSB 1ZSC 2ABE 2AW1 2AX2 2CA2 2CBA 2CBB 2CBC 2CBD 2CBE 2EU2 2EU3 2EZ7 2FMG 2FMZ 2FOQ 2FOS 2FOU 2FOV 2GEH 2H4N 2HD6 2VVA 2VVB 2WD2 2WD3 2WEG 2WEH 2WEJ 2WEO 2X7S 2X7U 3CA2 4CA2 4CAC 5CA2 5CAC 6CA2 7CA2 8CA2 9CA2
• 分子名称: CARBONIC ANHYDRASE 2, (9BETA,13ALPHA,14BETA,17ALPHA)-2-ETHYLESTRA-1(10),2,4-TRIENE-3,17-DIYL DISULFAMATE, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: lyase, cancer, sulfamate
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29839.37

構造登録者

Cozier, G.E.,Leese, M.P.,Lloyd, M.D.,Baker, M.D.,Thiyagarajan, N.,Acharya, K.R.,Potter, B.V.L. (登録日: 2010-03-03, 公開日: 2010-03-31, 最終更新日: 2023-12-20)

主引用文献

Cozier, G.E.,Leese, M.P.,Lloyd, M.D.,Baker, M.D.,Thiyagarajan, N.,Acharya, K.R.,Potter, B.V.L.
Structures of Human Carbonic Anhydrase II/Inhibitor Complexes Reveal a Second Binding Site for Steroidal and Non-Steroidal Inhibitors.
Biochemistry, 49:3464-, 2010

PubMed Abstract: Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon dioxide to hydrogen carbonate, and its role in maintaining pH balance has made it an attractive drug target. Steroidal sulfamate esters, inhibitors of the cancer drug target steroid sulfatase (STS), are sequestered in vivo by CA II in red blood cells, which may be the origin of their excellent drug properties. Understanding the structural basis of this is important for drug design. Structures of CA II complexed with 2-methoxyestradiol 3-O-sulfamate (3), 2-ethylestradiol 3,17-O,O-bis(sulfamate) (4), and 2-methoxyestradiol 17-O-sulfamate (5) are reported to 2.10, 1.85, and 1.64 A, respectively. Inhibitor 3 interacts with the active site Zn(II) ion through the 3-O-sulfamate, while inhibitors 4 and 5 bind through their 17-O-sulfamate. Comparison of the IC(50) values for CA II inhibition gave respective values of 56, 662, 2113, 169, 770, and 86 nM for estrone 3-O-sulfamate (1), 2-methoxyestradiol 3,17-O,O-bis(sulfamate) (2), 3, 4, 5, and 5'-((4H-1,2,4-triazol-4-yl)methyl)-3-chloro-2'-cyanobiphenyl-4-yl sulfamate (6), a nonsteroidal dual aromatase-sulfatase inhibitor. Inhibitors 2, 5, and 6 showed binding to a second adjacent site that is capable of binding both steroidal and nonsteroidal ligands. Examination of both IC(50) values and crystal structures suggests that 2-substituents on the steroid nucleus hinder binding via a 3-O-sulfamate, leading to coordination through a 17-O-sulfamate if present. These results underline the influence of small structural changes on affinity and mode of binding, the degree of flexibility in the design of sulfamate-based inhibitors, and suggest a strategy for inhibitors which interact with both the active site and the second adjacent binding site simultaneously that could be both potent and selective.

PubMed: 20297840
DOI: 10.1021/BI902178W

実験手法

X-RAY DIFFRACTION (1.89 Å)