PDBsum entry 3mvj

Transferase

PDB id

3mvj

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Contents

			Protein chains

					336 a.a. *


					20 a.a. *

			Ligands

					XFE ×2

			Waters ×231

* Residue conservation analysis

PDB id:

3mvj

Links

Name:

Transferase

Title:

Human cyclic amp-dependent protein kinase pka inhibitor complex

Structure:

Camp-dependent protein kinase catalytic subunit alpha. Chain: a, b, e. Synonym: pka c-alpha. Engineered: yes. Camp-dependent protein kinase inhibitor alpha. Chain: i, j, k. Synonym: pki-alpha, camp-dependent protein kinase inhibitor, muscle/brain isoform. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pka, pkaca, prkaca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes

Resolution:

2.49Å

R-factor:

0.217

R-free:

0.304

Authors:

J.Pandit,F.Vajdos

Key ref:

K.D.Freeman-Cook et al. (2010). Design of selective, ATP-competitive inhibitors of Akt. J Med Chem, 53, 4615-4622. PubMed id: 20481595

Date:

04-May-10

Release date:

02-Jun-10

PROCHECK

	Headers

	References

Protein chains

P17612 (KAPCA_HUMAN) - cAMP-dependent protein kinase catalytic subunit alpha from Homo sapiens

Seq: Struc:					351 a.a. 336 a.a.*

Protein chains

P61925 (IPKA_HUMAN) - cAMP-dependent protein kinase inhibitor alpha from Homo sapiens

Seq: Struc:					76 a.a. 20 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

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



		Enzyme reactions

Enzyme class:

Chains A, B, E: E.C.2.7.11.11 - cAMP-dependent protein kinase.

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

Reaction:

1.	L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
2.	L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein]	+	ATP	=	O-phospho-L-seryl-[protein]	+	ADP	+	H(+)

L-threonyl-[protein]	+	ATP	=	O-phospho-L-threonyl-[protein]	+	ADP	+	H(+)

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

reference

	J Med Chem 53:4615-4622 (2010)
PubMed id: 20481595

Design of selective, ATP-competitive inhibitors of Akt.
K.D.Freeman-Cook, C.Autry, G.Borzillo, D.Gordon, E.Barbacci-Tobin, V.Bernardo, D.Briere, T.Clark, M.Corbett, J.Jakubczak, S.Kakar, E.Knauth, B.Lippa, M.J.Luzzio, M.Mansour, G.Martinelli, M.Marx, K.Nelson, J.Pandit, F.Rajamohan, S.Robinson, C.Subramanyam, L.Wei, M.Wythes, J.Morris.

ABSTRACT

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21439031

L.Rosenbaum, G.Hinselmann, A.Jahn, and A.Zell (2011).
Interpreting linear support vector machine models with heat map molecule coloring.

J Cheminform, 3, 11.

21420856

R.Xu, A.Banka, J.F.Blake, I.S.Mitchell, E.M.Wallace, J.R.Bencsik, N.C.Kallan, K.L.Spencer, S.L.Gloor, M.Martinson, T.Risom, S.D.Gross, T.H.Morales, W.I.Wu, G.P.Vigers, B.J.Brandhuber, and N.J.Skelton (2011).
Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.

Bioorg Med Chem Lett, 21, 2335-2340.

PDB code:

3qkm

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.