PDBsum entry 3std

Lyase

PDB id

3std

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Contents

			Protein chains

					162 a.a. *

			Ligands

					MQ0 ×3

			Metals

					_CA ×2

			Waters ×422

* Residue conservation analysis

PDB id:

3std

Links

Name:

Lyase

Title:

Scytalone dehydratase and cyanocinnoline inhibitor

Structure:

Protein (scytalone dehydratase). Chain: a, b, c. Engineered: yes

Source:

Magnaporthe grisea. Organism_taxid: 148305. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Hexamer (from PQS)

Resolution:

1.65Å

R-factor:

0.194

R-free:

0.230

Authors:

J.M.Chen,S.L.Xu,Z.Wawrzak,G.S.Basarab,D.B.Jordan

Key ref:

J.M.Chen et al. (1998). Structure-based design of potent inhibitors of scytalone dehydratase: displacement of a water molecule from the active site. Biochemistry, 37, 17735-17744. PubMed id: 9922139 DOI: 10.1021/bi981848r

Date:

16-Oct-98

Release date:

16-Oct-99

PROCHECK

	Headers

	References

Protein chains

P56221 (SCYD_MAGO7) - Scytalone dehydratase from Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958)

Seq: Struc:					172 a.a. 162 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)



		Enzyme reactions

Enzyme class:

E.C.4.2.1.94 - scytalone dehydratase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

scytalone = 1,3,8-trihydroxynaphthalene + H2O

scytalone	=	1,3,8-trihydroxynaphthalene	+	H2O

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/bi981848r	Biochemistry 37:17735-17744 (1998)
PubMed id: 9922139

Structure-based design of potent inhibitors of scytalone dehydratase: displacement of a water molecule from the active site.
J.M.Chen, S.L.Xu, Z.Wawrzak, G.S.Basarab, D.B.Jordan.

ABSTRACT

Scytalone dehydratase (SD) is a molecular target of inhibitor design efforts aimed at protecting rice plants from the fungal disease caused by Magnaporthe grisea. As determined from X-ray diffraction data of an SD-inhibitor complex [Lundqvist et al. (1994) Structure (London) 2, 937-944], there is an extended hydrogen-bonding network between protein side chains, the inhibitor, and two bound water molecules. From models of SD complexed to quinazoline and benztriazine inhibitors, a new class of potent SD inhibitors involving the displacement of an active-site water molecule were designed. We were able to increase inhibitory potency by synthesizing compounds with a nitrile functionality displayed into the space occupied by one of the crystallographic water molecules. Sixteen inhibitors are compared. The net conversion of potent quinazoline and benztriazine inhibitors to cyanoquinolines and cyanocinnolines increased binding potency 2-20-fold. Replacement of the nitrile with a hydrogen atom lowered binding affinity 100-30,000-fold. X-ray crystallographic data at 1.65 A resolution on a SD-inhibitor complex confirmed that the nitrile functionality displaced the water molecule as intended and that a favorable orientation was created with tyrosines 30 and 50 which had been part of the hydrogen-bonding network with the water molecule. Additional data on inhibitors presented herein reveals the importance of two hydrogen-bonding networks toward inhibitory potency: one between Asn131 and an appropriately positioned inhibitor heteroatom and one between a bound water molecule and a second inhibitor heteroatom.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20345171

C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.

J Med Chem, 53, 5061-5084.

19754086

J.Michel, J.Tirado-Rives, and W.L.Jorgensen (2009).
Prediction of the water content in protein binding sites.

J Phys Chem B, 113, 13337-13346.

19778066

J.Michel, J.Tirado-Rives, and W.L.Jorgensen (2009).
Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization.

J Am Chem Soc, 131, 15403-15411.

19461869

S.Wong, R.E.Amaro, and J.A.McCammon (2009).
MM-PBSA Captures Key Role of Intercalating Water Molecules at a Protein-Protein Interface.

J Chem Theory Comput, 5, 422-429.

18366016

D.Katagiri, H.Fuji, S.Neya, and T.Hoshino (2008).
Ab initio protein structure prediction with force field parameters derived from water-phase quantum chemical calculation.

J Comput Chem, 29, 1930-1944.

17557328

S.K.Srivastava, D.Dube, V.Kukshal, A.K.Jha, K.Hajela, and R.Ramachandran (2007).
NAD+-dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: novel structure-function relationship and identification of a specific inhibitor.

Proteins, 69, 97.

17242738

Z.Li, and T.Lazaridis (2007).
Water at biomolecular binding interfaces.

Phys Chem Chem Phys, 9, 573-581.

16374623

A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.

J Mol Model, 12, 422-431.

14982794

K.L.White, J.M.Chen, N.A.Margot, T.Wrin, C.J.Petropoulos, L.K.Naeger, S.Swaminathan, and M.D.Miller (2004).
Molecular mechanisms of tenofovir resistance conferred by human immunodeficiency virus type 1 reverse transcriptase containing a diserine insertion after residue 69 and multiple thymidine analog-associated mutations.

Antimicrob Agents Chemother, 48, 992.

15355974

L.Xu, C.Li, A.J.Olson, and I.A.Wilson (2004).
Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening.

J Biol Chem, 279, 50555-50565.

PDB code:

1thz

12389036

D.Lim, and N.C.Strynadka (2002).
Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus.

Nat Struct Biol, 9, 870-876.

PDB codes:

1mwr 1mws 1mwt 1mwu 1mwx 1vqq

11590022

T.A.Fritz, D.Tondi, J.S.Finer-Moore, M.P.Costi, and R.M.Stroud (2001).
Predicting and harnessing protein flexibility in the design of species-specific inhibitors of thymidylate synthase.

Chem Biol, 8, 981-995.

PDB code:

1jg0

10913266

D.B.Jordan, G.S.Basarab, J.J.Steffens, R.S.Schwartz, and J.G.Doughty (2000).
Tight binding inhibitors of scytalone dehydratase: effects of site-directed mutations.

Biochemistry, 39, 8593-8602.

10636235

D.B.Jordan, and G.S.Basarab (2000).
Binding dynamics of two water molecules constrained within the scytalone dehydratase binding pocket.

Bioorg Med Chem Lett, 10, 23-26.

10694394

D.B.Jordan, Y.J.Zheng, B.A.Lockett, and G.S.Basarab (2000).
Stereochemistry of the enolization of scytalone by scytalone dehydratase.

Biochemistry, 39, 2276-2282.

10743955

D.I.Liao, G.S.Basarab, A.A.Gatenby, and D.B.Jordan (2000).
Selection of a potent inhibitor of trihydroxynaphthalene reductase by sorting disease control data.

Bioorg Med Chem Lett, 10, 491-494.

10097077

A.E.Nixon, S.M.Firestine, F.G.Salinas, and S.J.Benkovic (1999).
Rational design of a scytalone dehydratase-like enzyme using a structurally homologous protein scaffold.

Proc Natl Acad Sci U S A, 96, 3568-3571.

10386946

G.S.Basarab, D.B.Jordan, T.C.Gehret, R.S.Schwartz, and Z.Wawrzak (1999).
Design of scytalone dehydratase inhibitors as rice blast fungicides: derivatives of norephedrine.

Bioorg Med Chem Lett, 9, 1613-1618.

10498198

L.D.Jennings, Z.Wawrzak, D.Amorose, R.S.Schwartz, and D.B.Jordan (1999).
A new potent inhibitor of fungal melanin biosynthesis identified through combinatorial chemistry.

Bioorg Med Chem Lett, 9, 2509-2514.

10382670

Z.Wawrzak, T.Sandalova, J.J.Steffens, G.S.Basarab, T.Lundqvist, Y.Lindqvist, and D.B.Jordan (1999).
High-resolution structures of scytalone dehydratase-inhibitor complexes crystallized at physiological pH.

Proteins, 35, 425-439.

PDB codes:

4std 5std 6std 7std

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.