2Y5G

FACTOR XA - CATION INHIBITOR COMPLEX

Summary for 2Y5G

• Entry DOI: 10.2210/pdb2y5g/pdb
• Related: 1C5M 1EZQ 1F0R 1F0S 1FAX 1FJS 1G2L 1G2M 1HCG 1IOE 1IQE 1IQF 1IQG 1IQH 1IQI 1IQJ 1IQK 1IQL 1IQM 1IQN 1KSN 1KYE 1LPG 1LPK 1LPZ 1LQD 1MQ5 1MQ6 1MSX 1NFU 1NFW 1NFX 1NFY 1NL8 1P0S 1V3X 1WU1 1XKA 1XKB 1Z6E 2BMG 2BOH 2BOK 2BQ6 2BQ7 2BQW 2CJI 2FZZ 2G00 2GD4 2J2U 2J34 2J38 2J4I 2J94 2J95 2JKH 2UWL 2UWO 2UWP 2VH0 2VH6 2VVC 2VVU 2VVV 2VWL 2VWM 2VWN 2VWO 2W26 2W3I 2W3K 2WYG 2WYJ 2XBV 2XBW 2XBX 2XBY 2XC0 2XC4 2XC5 2Y5F 2Y5H
• Descriptor: ACTIVATED FACTOR XA HEAVY CHAIN, FACTOR X LIGHT CHAIN, 3-[(3AS,4R,5S,8AS,8BR)-4-[5-(5-CHLOROTHIOPHEN-2-YL)-1,3-OXAZOL-2-YL]-1,3-DIOXO-4,6,7,8,8A,8B-HEXAHYDRO-3AH-PYRROLO[3,4-A]PYRROLIZIN-2-YL]PROPYL-TRIMETHYL-AZANIUM, ... (5 entities in total)
• Functional Keywords: blood clotting, plasma, zymogen, hydrolase, blood coagulation, hydroxylation, serine protease, egf-like domain
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32832.63

Authors

Banner, D.W.,Salonen, L.M.,Holland, M.C.,Haap, W.,Benz, J.,Diederich, F. (deposition date: 2011-01-13, release date: 2011-12-28, Last modification date: 2024-11-06)

Primary citation

Salonen, L.M.,Holland, M.C.,Kaib, P.S.,Haap, W.,Benz, J.,Mary, J.L.,Kuster, O.,Schweizer, W.B.,Banner, D.W.,Diederich, F.
Molecular Recognition at the Active Site of Factor Xa: Cation-Pi Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water.
Chemistry, 18:213-, 2012

PubMed Abstract: Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cation-π interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structure-activity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to K(i)=2 nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes.

PubMed: 22162109
DOI: 10.1002/CHEM.201102571

Experimental method

X-RAY DIFFRACTION (1.29 Å)