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PDB Research Experience Summer Intern Presentation July 14, 2009 Heidi Chen Jane Hand Mira Patel Mike Ticchio. Outline. Projects & Goals Peptide Reference Dictionary Antibiotics Examples Inhibitors Second Life Future. Projects & Goals. Peptide Reference Dictionary

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Outline
Outline

  • Projects & Goals

  • Peptide Reference Dictionary

    • Antibiotics

      • Examples

    • Inhibitors

  • Second Life

  • Future


Projects goals
Projects & Goals

  • Peptide Reference Dictionary

    • Gather info for a searchable dictionary

    • Organize information about antibiotics and inhibitors from various databases

  • Second Life

    • Incorporate ”Molecule of the Month” into Second Life


Antibiotics
Antibiotics

  • Given a list from Miri (EBI)

  • 45 antibiotics + PDB instances

  • expanded the list to 73 antibiotics

  • analyzed a total of 163 PDB instances




Databases
Databases

SciFinder

MeSH

Merck

Belstein

KEGG

Drugbank

  • Uniprot

  • PubChem

  • ChemSpider

  • chEBI

  • chemDB

  • ChemBank

  • Norine

  • ABX Guide

  • Bactibase

  • Novel Antibiotics


What we found
What we found..

CAS Registry Number

various IDS (KEGG, PubChem, etc.)

synonyms

functions

Ontology (chEBI, KEGG Brite, MeSH)

SMILES



Pdb instances
PDB Instances

read primary citation

record functions, often referencing other papers

check for consistency between primary citation, PDB file, and other databases


Issues
Issues

PubChem

multiple entries for the same compound

no annotation

ChemSpider

could not search database with ChemSpider ID

resolved


Norine
Norine

database for nonribosomal peptides

provdes information about structure, function, taxonomy

various links to PDB, Uniprot



Seqres of the PDB Entries

DAPTOMYCIN

1t5m

1t5n

: DKA TRP DSG ASP THR GLY ORN ASP DAL ASP GLY DSN MEG KYN

1xt7 : DKA TRP ASN ASP THR GLY ORN ASP DAL ASP GLY DSN LME KYN

D-ASPARAGINE (R chirality)

ASPARAGINE (S chirality)

DSG vs. ASN


Comparison of PDB Entries

1xt7 vs.1t5m, 1t5n

R chirality

1xt7: V. Ramesh et al

S chirality


Seqres of the PDB Entries

1t5m

1t5n

: DKA TRP DSG ASP THR GLY ORN ASP DAL ASP GLY DSN MEG KYN

1xt7: DKA TRP ASN ASP THR GLY ORN ASP DAL ASP GLY DSN LME KYN

2S,3S

LME

(3R)-3-METHYL-L-GLUTAMIC ACID

MEG

(2S,3R)-3-METHYL-GLUTAMIC ACID

MEG vs. LME


Comparison of PDB Entries

1xt7 vs.1t5m, 1t5n

3R chirality

1xt7: V. Ramesh et al


Final sequence of daptomycin
Final Sequence of Daptomycin

1t5m

1t5n

: DKA TRP DSG ASP THR GLY ORN ASP DAL ASP GLY DSN MEG KYN

1xt7: DKA TRP ASN ASP THR GLY ORN ASP DAL ASP GLY DSN LME KYN

DKA TRP DSG ASP THR GLY ORN ASP DAL ASP GLY DSN LME KYN


Balhimycin Comparison

1go6

KEGG

C66H73Cl2N9O24

C66H75Cl2N9O25

1go6: G. Sheldrick et al



Nisin
Nisin

  • Type-A(I) Lantibiotic

  • Used in food as a preservative

  • Unusual AA's such as lanthionine, methyllanthionine, Dha, Dhb

Asaduzzaman et. al


Nisin1
Nisin

  • Traditional antibiotics have specific modes of action

  • Lantibiotics have more diverse modes of action

  • Binds lipid II and forms a stable pore

  • Inhibits in vitro lipid II synthesis

Asaduzzaman et. al


Nisin2
Nisin

  • Outlook on Nisin and other Lantibiotics

    • Has no known toxicity to humans

    • Works against vancomycin-resistant bacteria

    • In the preclinical stages of medical application

    • Threats of bioterrorism

Asaduzzaman et. al


What we re doing now
What we're doing now...

  • Crosschecked each other's work

  • Started the first of two inhibitor/special peptide lists

    • combined vs. poly/split

    • 250 inhibitors with 394 PDB instances

  • Same format as antibiotics


What we re doing now1
What we're doing now...

  • Chem Spider

  • CheBI

  • ChemDB

  • ChemBank

  • eMolecules

  • Inhibitor Source Book

  • Scifinder

  • MeSH

  • Merck

  • Beilstein

  • KEGG

  • DrugBank

  • PubChem


What we re doing now2
What we're doing now...

  • Different approach to finding some CAS RNs

  • IUPAC names are difficult to search with

  • Can't use CAS RN to search in a few major databases

  • SMILEs don't work

  • Substructure search is possible


Second life
Second Life

  • Created by Linden Labs

  • Virtual world to create a second life for yourself

  • Many uses

    • Education: Research/ Teaching/ Showcasing work

    • Embassies

    • Entertainment: Music/ Sports/ Art Exhibits/ Theater

    • Religion


Second life1
Second Life

  • Laboratory by Nature on the Elucian Islands

  • Meetings about ongoing various projects

  • Goal: Make interactive protein models

    • Highlight active sites and any residues of special interest

    • Test model: Myoglobin



Second life3
Second Life

  • Prims

  • Sculpties

  • Textures


Continuing second life
Continuing Second Life

  • Become more familiar with building in SL

  • Create an interactive molecule

  • Revamp and decorate our lab


Timeline
Timeline

  • June 1st – June 15th : Training

  • June 16th – July 1st : Antibiotics & Checking

  • July 2nd – end of July: Inhibitors & Checking

  • End of July – August 7th: Uncombined Inhibitors & Final Presentation


Thanks
Thanks!

  • Thanks to Dr. Helen Berman, Dr. Shuchi Dutta, Dr. Maggie Gabanyi, Hyunmi, and James

  • Questions?


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