Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis: mechanism and novel inhibitor design

Structure
Kerim BabaogluStephen W White

Abstract

Dihydropterate synthase (DHPS) is the target for the sulfonamide class of antibiotics, but increasing resistance has encouraged the development of new therapeutic agents against this enzyme. One approach is to identify molecules that occupy the pterin binding pocket which is distinct from the pABA binding pocket that binds sulfonamides. Toward this goal, we present five crystal structures of DHPS from Bacillus anthracis, a well-documented bioterrorism agent. Three DHPS structures are already known, but our B. anthracis structures provide new insights into the enzyme mechanism. We show how an arginine side chain mimics the pterin ring in binding within the pterin binding pocket. The structures of two substrate analog complexes and the first structure of a DHPS-product complex offer new insights into the catalytic mechanism and the architecture of the pABA binding pocket. Finally, as an initial step in the development of pterin-based inhibitors, we present the structure of DHPS complexed with 5-nitro-6-methylamino-isocytosine.

References

Feb 9, 1976·Biochemical and Biophysical Research Communications·G B HendersonF M Huennekens
Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Apr 25, 1997·Journal of Molecular Biology·I C HampeleR L Then
Jun 1, 1997·Nature Structural Biology·A AchariD K Stammers
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·R M Esnouf
May 18, 1999·Biochemical and Biophysical Research Communications·H G Vinnicombe, J P Derrick
Jul 4, 2001·Veterinary Research·O Sköld
Aug 11, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ola Sköld
Aug 30, 2001·Progress in Nucleic Acid Research and Molecular Biology·L H Matherly
Jun 25, 2003·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Maria JönssonGöte Swedberg
Oct 14, 2003·Drug Discovery Today·Ronald A Greenfield, Michael S Bronze
Jul 17, 2004·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Amera GibreelDiane E Taylor
Jan 1, 1993·Acta Crystallographica. Section D, Biological Crystallography·V S Lamzin, K S Wilson
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Jan 1, 1997·Methods in Enzymology·E A Merritt, D J Bacon
Dec 18, 2009·Expert Review of Anti-infective Therapy·Ola Sköld
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Jul 31, 2007·Future Microbiology·Yongyuth YuthavongPenchit Chitnumsub
Jul 19, 2013·Future Medicinal Chemistry·Dalia I HammoudehRichard E Lee
Aug 13, 2014·European Journal of Medicinal Chemistry·Hany S IbrahimMarwa M Abdel-Aziz
May 13, 2009·Journal of Chemical Information and Modeling·Kirk E HevenerRichard E Lee
Nov 11, 2009·Journal of Medicinal Chemistry·Kirk E HevenerRichard E Lee
May 7, 2010·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Sandeep ChhabraJames D Swarbrick
Sep 16, 2011·Bioconjugate Chemistry·Ying ZhaoRichard E Lee
Oct 4, 2012·Journal of Biomolecular Structure & Dynamics·Wen-Ting ChuHong-Xing Zhang
Jun 1, 2007·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Michelle Wright ValderasWilliam W Barrow
Mar 3, 2012·Science·Mi-Kyung YunStephen W White
Apr 10, 2013·Analytical Biochemistry·Xiao LiangSuxia Zhang
Dec 1, 2006·Analytical Biochemistry·Ross T FernleyIan Macreadie
Jul 18, 2016·Bioorganic & Medicinal Chemistry Letters·Ying ZhaoRichard E Lee
Jun 24, 2017·Organic & Biomolecular Chemistry·Warot ChotpatiwetchkulM Paul Gleeson
Apr 10, 2018·Future Medicinal Chemistry·Marcio V Bertacine DiasSair M Chavez-Pacheco
Aug 16, 2018·Organic & Biomolecular Chemistry·Nathjanan JongkonM Paul Gleeson
Jul 16, 2019·MedChemComm·Shannon Lynn Kordus, Anthony David Baughn
Apr 19, 2017·FEMS Microbiology Reviews·Timothy J Foster
Nov 25, 2017·Chemistry : a European Journal·Matthew L DennisJames D Swarbrick
Jun 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rafik KaramanZeinab Breijyeh
Aug 15, 2018·Scientific Reports·Suprabhat MukherjeeSanti P Sinha Babu
Jun 26, 2020·The Journal of Physical Chemistry. B·Deepika NambiarElizabeth E Howell
Mar 22, 2014·ACS Chemical Biology·Dalia I HammoudehStephen W White
Mar 18, 2008·Biochimica Et Biophysica Acta·Michelle Wright ValderasPaul F Cook
Aug 19, 2007·Journal of Medicinal Chemistry·Brad C BennettChris G Dealwis
Sep 29, 2021·Journal of Biomolecular Structure & Dynamics·Bratin Kumar Das, Debashree Chakraborty

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