Target Information

Target General Information

Target ID

T33193 (Former ID: TTDS00212)

Target Name

Bacterial Penicillin binding protein 3 (Bact mrcA)

Synonyms

mrcA; Peptidoglycan synthetase ftsI; Peptidoglycan glycosyltransferase 3; Penicillin-binding protein 3; PSPB20; PBP-3; PBP 3

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Gene Name

Bact mrcA

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Respiratory infection [ICD-11: CA07-CA4Z]

Urinary tract infection [ICD-11: GC08]

Function

Cell wall formation. Essential for the formation of a septum of the murein sacculus. Synthesis of cross-linked peptidoglycan from the lipid intermediates.

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BioChemical Class

Hexosyltransferase

UniProt ID

FTSI_ECOLI

EC Number

EC 3.4.16.4

Sequence

MKAAAKTQKPKRQEEHANFISWRFALLCGCILLALAFLLGRVAWLQVISPDMLVKEGDMR
SLRVQQVSTSRGMITDRSGRPLAVSVPVKAIWADPKEVHDAGGISVGDRWKALANALNIP
LDQLSARINANPKGRFIYLARQVNPDMADYIKKLKLPGIHLREESRRYYPSGEVTAHLIG
FTNVDSQGIEGVEKSFDKWLTGQPGERIVRKDRYGRVIEDISSTDSQAAHNLALSIDERL
QALVYRELNNAVAFNKAESGSAVLVDVNTGEVLAMANSPSYNPNNLSGTPKEAMRNRTIT
DVFEPGSTVKPMVVMTALQRGVVRENSVLNTIPYRINGHEIKDVARYSELTLTGVLQKSS
NVGVSKLALAMPSSALVDTYSRFGLGKATNLGLVGERSGLYPQKQRWSDIERATFSFGYG
LMVTPLQLARVYATIGSYGIYRPLSITKVDPPVPGERVFPESIVRTVVHMMESVALPGGG
GVKAAIKGYRIAIKTGTAKKVGPDGRYINKYIAYTAGVAPASQPRFALVVVINDPQAGKY
YGGAVSAPVFGAIMGGVLRTMNIEPDALTTGDKNEFVINQGEGTGGRS

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Drugs and Modes of Action

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Approved Drug(s)

[+] 7 Approved Drugs

Aztreonam

Drug Info

Approved

Bacterial infection

[2]

Cefmenoxime

Drug Info

Approved

Bacterial infection

[2]

Cefmetazole

Drug Info

Approved

Bacterial infection

[3]

Cefotiam

Drug Info

Approved

Respiratory tract infection

[2], [4]

Latamoxef

Drug Info

Approved

Bacterial infection

[5]

Mezlocillin

Drug Info

Approved

Urinary tract infection

[4], [6]

Moxalactam Disodium

Drug Info

Approved

Bacterial infection

[4]

Mode of Action

[+] 4 Modes of Action

Binder

[+] 8 Binder drugs

Aztreonam

Drug Info

[1]

Cefmenoxime

Drug Info

[8]

Cefmetazole

Drug Info

[5]

Cefotiam

Drug Info

[9]

Latamoxef

Drug Info

[5]

Mezlocillin

Drug Info

[10]

Benzylpenicillin

Drug Info

[12]

Acylureido penicillin mezlocillin

Drug Info

[13]

Modulator

[+] 1 Modulator drugs

Moxalactam Disodium

Drug Info

[11]

Antagonist

[+] 1 Antagonist drugs

Cephalosporin C

Drug Info

[14]

Inhibitor

[+] 1 Inhibitor drugs

PCNOTAXIME GROUP

Drug Info

[15]

Drug Binding Sites of Target

Top

Ligand Name: AIC499 (bound)

Ligand Info

Structure Description

Crystal structure of PBP3 from E. coli in complex with AIC499

PDB:7ONW

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

[16]

PDB Sequence

LRVQQVSTSR

⁷¹

GMITDRSGRP

⁸¹

LAVSVPVKAI

⁹¹

WADPKEVHDA

¹⁰¹

GGISVGDRWK

¹¹¹

ALANALNIPL

¹²¹

DQLSARINAN

¹³¹

PKGRFIYLAR

¹⁴¹

QVNPDMADYI

¹⁵¹

KKLKLPGIHL

¹⁶¹

REESRRYYPS

¹⁷¹

GEVTAHLIGF

¹⁸¹

TNVDSQGIEG

¹⁹¹

VEKSFDKWLT

²⁰¹

GQAAHNLALS

²³⁵

IDERLQALVY

²⁴⁵

RELNNAVAFN

²⁵⁵

KAESGSAVLV

²⁶⁵

DVNTGEVLAM

²⁷⁵

ANSPSYNPNN

²⁸⁵

LSGTPKEAMR

²⁹⁵

NRTITDVFEP

³⁰⁵

GSTVKPMVVM

³¹⁵

TALQRGVVRE

³²⁵

NSVLNTIPYR

³³⁵

INGHEIKDVA

³⁴⁵

RYSELTLTGV

³⁵⁵

LQKSSNVGVS

³⁶⁵

KLALAMPSSA

³⁷⁵

LVDTYSRFGL

³⁸⁵

GKATNLGLVG

³⁹⁵

ERSGLYPQKQ

⁴⁰⁵

RWSDIERATF

⁴¹⁵

SFGYGLMVTP

⁴²⁵

LQLARVYATI

⁴³⁵

GSYGIYRPLS

⁴⁴⁵

ITKVDPPVPG

⁴⁵⁵

ERVFPESIVR

⁴⁶⁵

TVVHMMESVA

⁴⁷⁵

LPGGGGVKAA

⁴⁸⁵

IKGYRIAIKT

⁴⁹⁵

GTAKKVGPDG

⁵⁰⁵

RYINKYIAYT

⁵¹⁵

AGVAPASQPR

⁵²⁵

FALVVVINDP

⁵³⁵

QAGKYYGGAV

⁵⁴⁵

SAPVFGAIMG

⁵⁵⁵

GVLRTMNIEP

⁵⁶⁵

DALTT

Residue

Distance (Å)

GLU304

2.273

GLY306

3.225

SER307

1.458

THR308

4.974

LYS310

3.793

VAL344

3.264

SER359

3.315

ASN361

3.281

PHE417

3.100

GLY418

3.590

TYR419

3.319

LYS494

4.397

Residue

Distance (Å)

THR495

2.547

GLY496

3.358

THR497

2.360

ALA498

3.490

LYS499

3.004

TYR507

3.987

TYR511

4.135

TYR540

4.474

TYR541

3.315

GLY542

3.611

GLY543

4.075

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Similarity Proteins

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Similarity Proteins

There is no similarity protein (E value < 0.005) for this target

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Penicillin-binding protein PBP2 of Escherichia coli localizes preferentially in the lateral wall and at mid-cell in comparison with the old cell pole. Mol Microbiol. 2003 Jan;47(2):539-47.

REF 2

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 3

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 050637.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

Clinical relevance of antibiotic-induced endotoxin release in patients undergoing hepatic resection. World J Surg. 1999 Jan;23(1):75-9.

REF 6

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 050549.

REF 7

ClinicalTrials.gov (NCT03377426) LYS228 PK, Clinical Response, Safety and Tolerability in Patients With Complicated Urinary Tract Infection (cUTI). U.S. National Institutes of Health.

REF 8

In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity. Antimicrob Agents Chemother. 1988 May;32(5):693-701.

REF 9

Genetic analyses of beta-lactamase negative ampicillin-resistant strains of Haemophilus influenzae isolated in Okinawa, Japan. Jpn J Infect Dis. 2006 Feb;59(1):36-41.

REF 10

Bactericidal effect of piperacillin alone and combined. Presse Med. 1986 Dec 20;15(46):2297-302.

REF 11

Moxalactam (6059-S), a new 1-oxa-beta-lactam: binding affinity for penicillin-binding proteins of Escherichia coli K-12.

REF 12

Association of amino acid substitutions in penicillin-binding protein 3 with beta-lactam resistance in beta-lactamase-negative ampicillin-resistant Haemophilus influenzae. Antimicrob Agents Chemother. 2001 Jun;45(6):1693-9.

REF 13

Microbiology, pharmacology, and clinical use of mezlocillin sodium. Pharmacotherapy. 1982 Nov-Dec;2(6):300-12.

REF 14

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 15

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 16

Interaction Mode of the Novel Monobactam AIC499 Targeting Penicillin Binding Protein 3 of Gram-Negative Bacteria. Biomolecules. 2021 Jul 19;11(7):1057.

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