Human Protein Tyrosine Phosphatases (PTPs)

Protein tyrosine phosphatases (PTPs) play a critical role regulating cell signaling by selectively dephosphorylating their substrates. So far our laboratory has released 22 human high resolution crystal structures which, together with prior structural knowledge, results in an excellent structural coverage of the classical PTP family. A recent structural analysis carried out in our laboratory compared the existing structural information available for this enzyme family [1]. The comparison revealed that despite their largely conserved fold, surface properties of PTPs are strikingly diverse. A number of unique and shared features has been identified that offers an excellent basis for structure-based design efforts of target specific inhibitors. Many PTPs have been recognized as potential targets [2] for the development of new therapies and the development of selective inhibitors is an ongoing effort in our laboratory.

1. Barr et al.. Large-Scale Structural Analysis of the Classical Human Protein Tyrosine Phosphatome. Cell (2009) 136(2):352-363.

2. Tautz et al.. Targeting the PTPome in human disease. Expert Opin. Ther. Targets. (2006) 10(1):157-77.

3. Tonks. Protein Tyrosine Phosphatases: From Gene to Function to Disease. Nat Rev Mol Cell Biol. (2006) 7(11):833-846.

About the image: Similar to early comparisons of different species that led to the establishment of phylogenetic trees, high resolution structural information can be used to identify unique as well as shared structural properties that can be explored and cluster members of a enzyme family into a tree based on molecular properties. The structural comparison of PTPs revealed that many features cannot be reliably predicted from sequence analysis alone. The phosphatase images are coloured according to the surface electrostatic potential using ICM.

PTP Domain Structural Coverage

The human genome contains 107 PTPs grouped into four distinct families: Class I cysteine-based PTPs constitute the largest family. They are divided into 38 “classical” tyrosine specific PTPs and 61 dual specificity phosphatases (DUSPs) [4]. The classical PTPs are one of the most comprehensively structurally covered protein families: 32 structures of the 49 D1/D2 domains are currently available. PTPs share a highly conserved overall fold but have very diverse protein surface properties.

4. Alonso et al.. Protein tyrosine phosphatases in the human genome. Cell (2004) 117(6):699-711.

Structural coverage of the human PTP family: Catalytic domains with known three dimensional structure are highlighted by a dot. Dots with a yellow center indicate structures released by our laboratory.

Recent human phosphatase domain structure depositions in the PDB

PDB code	Release date	Phosphatase	Species	Description	Sector
3EU0	11.Nov.2008	PTPN1	Human	Crystal structure of the S-nitrosylated Cys215 of PTP1B	Academia
2ZMM	07.Oct.2008	PTPN1	Human	Crystal structure of PTP1B-inhibitor complex, 4-bromo-3-(carboxymethoxy)- 5-{3-[cyclohexyl (methylcarbamoyl) amino]phenyl} thiophene-2- carboxylic acid	Industry
2ZN7	07.Oct.2008	PTPN1	Human	Crystal structure of PTP1B-inhibitor complex, 4-bromo-3-(carboxymethoxy)- 5-{3-[cyclohexyl (phenylcarbonyl) amino]phenyl} thiophene-2- carboxylic acid	Industry
3D9C	23.Sep.2008	PTPN1	Human	Crystal Structure PTP1B complex with aryl Seleninic acid	Academia
2QDC	24.Jun.2008	PTPN7	Human	Crystal structure of the HePTP catalytic domain D236A mutant	Academia
2QDM	24.Jun.2008	PTPN7	Human	Crystal structure of the HePTP catalytic domain C270S/D236A/Q314A mutant	Academia
2QDP	24.Jun.2008	PTPN7	Human	Crystal structure of the HePTP catalytic domain C270S mutant crystallized in ammonium acetate	Academia
3CWE	10.Jun.2008	PTPN1	Human	PTP1B in complex with a phosphonic acid inhibitor	Industry
2JJD	08.Apr.2008	PTPRE	Human	pProtein tyrosine phosphatase, receptor type, E isoform	SGC Oxford

PTP Structures deposited by SGC

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HUGO name	Protein Name	PDB code
PTPRK	RPTPκ	2C7S
PTPRT	RPTPρ	2OOQ
PTPRE	RPTPε	2JJD	coming soon
PTPRG	RPTPγ	2NLK
PTPRG	RPTPγ	2H4V
PTPRB	RPTPβ	2AHS
PTPRJ	DEP1	2CFV, 2NZ6
PTPRO	GLEPP1	2GJT
PTPRR	PCPTP1	2A8B
PTPN5	STEP	2BIJ
PTPN5	STEP	2CJZ
PTPN5	STEP	2BV5

HUGO name	Protein Name	PDB code
PTPN7	HePTP	2A3K
PTPRN2	IA2β	2QEP
PTPN11	SHP2	3B7O
PTPN9	MEG2	2PA5
PTPN3	PTPH1	2B49
PTPN4	MEG1	2I75
PTPN18	BDP1	2OC3
PTPN22	LYP	2P6X
PTPN14	PTPD2	2BZL