5U0Z

E. coli dihydropteroate synthase complexed with an 8-mercaptoguanine derivative

Summary for 5U0Z

• Entry DOI: 10.2210/pdb5u0z/pdb
• Related: 5U0V 5U0W 5U0X 5U0Y 5U10 5U11 5U12 5U13 5U14
• Descriptor: Dihydropteroate synthase, (2R)-[(2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)sulfanyl](phenyl)acetic acid (3 entities in total)
• Functional Keywords: e. coli, dhps, complex, pterin site, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli O6:H1 (strain CFT073 / ATCC 700928 / UPEC)
• Total number of polymer chains: 2
• Total formula weight: 62227.11

Authors

Dennis, M.L.,Peat, T.S.,Swarbrick, J.D. (deposition date: 2016-11-27, release date: 2017-12-06, Last modification date: 2023-10-04)

Primary citation

Dennis, M.L.,Lee, M.D.,Harjani, J.R.,Ahmed, M.,DeBono, A.J.,Pitcher, N.P.,Wang, Z.C.,Chhabra, S.,Barlow, N.,Rahmani, R.,Cleary, B.,Dolezal, O.,Hattarki, M.,Aurelio, L.,Shonberg, J.,Graham, B.,Peat, T.S.,Baell, J.B.,Swarbrick, J.D.
8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase.
Chemistry, 24:1922-1930, 2018

PubMed Abstract: Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-μm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure-activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.

PubMed: 29171692
DOI: 10.1002/chem.201704730

Experimental method

X-RAY DIFFRACTION (2.29 Å)